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  • 1.
    Augier, Eric
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Barbier, Estelle
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Dulman, Russell S
    Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois, Chicago, IL 60612, USA.
    Licheri, Valentina
    Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Göteborg, 413 90 Göteborg, Sweden.
    Augier, Gaëlle
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Domi, Esi
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Barchiesi, Riccardo
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Farris, Sean
    The Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX 78712, USA.
    Nätt, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Mayfield, R Dayne
    The Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX 78712, USA.
    Adermark, Louise
    Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Göteborg, 413 90 Göteborg, Sweden.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    A molecular mechanism for choosing alcohol over an alternative reward.2018In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 360, no 6395, p. 1321-1326Article in journal (Refereed)
    Abstract [en]

    Alcohol addiction leads to increased choice of alcohol over healthy rewards. We established an exclusive choice procedure in which ~15% of outbred rats chose alcohol over a high-value reward. These animals displayed addiction-like traits, including high motivation to obtain alcohol and pursuit of this drug despite adverse consequences. Expression of the γ-aminobutyric acid (GABA) transporter GAT-3 was selectively decreased within the amygdala of alcohol-choosing rats, whereas a knockdown of this transcript reversed choice preference of rats that originally chose a sweet solution over alcohol. GAT-3 expression was selectively decreased in the central amygdala of alcohol-dependent people compared to those who died of unrelated causes. Impaired GABA clearance within the amygdala contributes to alcohol addiction, appears to translate between species, and may offer targets for new pharmacotherapies for treating this disorder.

  • 2.
    Barbier, Estelle
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Johnstone, A. L.
    University of Miami, FL 33136 USA.
    Khomtchouk, B. B.
    University of Miami, FL 33136 USA.
    Tapocik, J. D.
    NIAAA, MD USA.
    Pitcairn, C.
    NIAAA, MD USA.
    Rehman, F.
    NIAAA, MD USA.
    Augier, Eric
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Borich, A.
    NIAAA, MD USA.
    Schank, J. R.
    University of Georgia, GA 30602 USA.
    Rienas, C. A.
    University of Miami, FL 33136 USA.
    Van Booven, D. J.
    University of Miami, FL 33136 USA.
    Sun, H.
    NIAAA, MD USA.
    Nätt, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Wahlestedt, C.
    University of Miami, FL 33136 USA; University of Miami, FL 33136 USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. NIAAA, MD USA.
    Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM22017In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 22, no 12, p. 1746-1758Article in journal (Refereed)
    Abstract [en]

    Epigenetic processes have been implicated in the pathophysiology of alcohol dependence, but the specific molecular mechanisms mediating dependence-induced neuroadaptations remain largely unknown. Here, we found that a history of alcohol dependence persistently decreased the expression of Prdm2, a histone methyltransferase that monomethylates histone 3 at the lysine 9 residue (H3K9me1), in the rat dorsomedial prefrontal cortex (dmPFC). Downregulation of Prdm2 was associated with decreased H3K9me1, supporting that changes in Prdm2 mRNA levels affected its activity. Chromatin immunoprecipitation followed by massively parallel DNA sequencing showed that genes involved in synaptic communication are epigenetically regulated by H3K9me1 in dependent rats. In non-dependent rats, viral-vector-mediated knockdown of Prdm2 in the dmPFC resulted in expression changes similar to those observed following a history of alcohol dependence. Prdm2 knockdown resulted in increased alcohol self-administration, increased aversion-resistant alcohol intake and enhanced stress-induced relapse to alcohol seeking, a phenocopy of postdependent rats. Collectively, these results identify a novel epigenetic mechanism that contributes to the development of alcohol-seeking behavior following a history of dependence.

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  • 3.
    Carleial, Samuel
    et al.
    Univ Konstanz, Germany.
    Nätt, Daniel
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Unternährer, Eva
    Univ Konstanz, Germany; Univ Basel, Switzerland.
    Elbert, Thomas
    Univ Konstanz, Germany; Vivo Int EV, Germany.
    Robjant, Katy
    Vivo Int EV, Germany.
    Wilker, Sarah
    Vivo Int EV, Germany; Univ Bielefeld, Germany.
    Vukojevic, Vanja
    Univ Basel, Switzerland.
    Kolassa, Iris-Tatjana
    Vivo Int EV, Germany; Ulm Univ, Germany.
    Zeller, Anja C.
    Univ Konstanz, Germany; Vivo Int EV, Germany.
    Koebach, Anke
    Univ Konstanz, Germany.
    DNA methylation changes following narrative exposure therapy in a randomized controlled trial with female former child soldiers2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 18493Article in journal (Refereed)
    Abstract [en]

    The aftermath of traumatization lives on in the neural and epigenetic traces creating a momentum of affliction in the psychological and social realm. Can psychotherapy reorganise these memories through changes in DNA methylation signatures? Using a randomised controlled parallel group design, we examined methylome-wide changes in saliva samples of 84 female former child soldiers from Eastern DR Congo before and six months after Narrative Exposure Therapy. Treatment predicted differentially methylated positions (DMPs) related to ALCAM, RIPOR2, AFAP1 and MOCOS. In addition, treatment associations overlapped at gene level with baseline clinical and social outcomes. Treatment related DMPs are involved in memory formation-the key agent in trauma focused treatments-and enriched for molecular pathways commonly affected by trauma related disorders. Results were partially replicated in an independent sample of 53 female former child soldiers from Northern Uganda. Our results suggest a molecular impact of psychological treatment in women with war-related childhood trauma.

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  • 4.
    Elfwing, Magnus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Nätt, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Goerlich-Jansson, Vivian C.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology. Department of Animals in Science and Society, University of Utrecht, Faculty of Veterinary Medicine, Utrecht, The Netherlands.
    Persson, Mia
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Hjelm, Jonas
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Early stress causes sex-specific, life-long changes in behaviour, levels of gonadal hormones, and gene expression in chickens2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 5, article id e0125808Article in journal (Refereed)
    Abstract [en]

    Early stress can have long-lasting phenotypic effects. Previous research shows that male and female chickens differ in many behavioural aspects, and respond differently to chronic stress. The present experiment aimed to broadly characterize long-term sex differences in responses to brief events of stress experienced during the first weeks of life. Chicks from a commercial egg-laying hybrid were exposed to stress by inducing periods of social isolation during their first three weeks of life, followed by a broad behavioural, physiological and genomic characterization throughout life. Early stressed males, but not females, where more anxious in an open field-test, stayed shorter in tonic immobility and tended to have delayed sexual maturity, as shown by a tendency for lower levels of testosterone compared to controls. While early stressed females did not differ from non-stressed in fear and sexual maturation, they were more socially dominant than controls. The differential gene expression profile in hypothalamus was significantly correlated from 28 to 213 days of age in males, but not in females. In conclusion, early stress had a more pronounced long-term effect on male than on female chickens, as evidenced by behavioral, endocrine and genomic responses. This may either be attributed to inherent sex differences due to evolutionary causes, or possibly to different stress related selection pressures on the two sexes during commercial chicken breeding.

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  • 5.
    Goerlich, Vivian C.
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Nätt, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Elfwing, Magnus
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Macdonald, Barry
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Transgenerational effects of early experience on acute stress reactions in behaviour, steroid hormones and gene expression in the precocial chicken2012In: Hormones and Behavior, ISSN 0018-506X, E-ISSN 1095-6867, Vol. 61, no 5, p. 711-718Article in journal (Refereed)
    Abstract [en]

    Stress during early life can profoundly influence an individual’s phenotype. Effects can manifest in the short-term as well as later in life and even in subsequent generations. Transgenerational effects of stress are potentially mediated via modulation of the hypothalamic-pituitary-adrenal axis (HPA) as well as epigenetic mechanisms causing heritable changes in gene expression. To investigate these pathways we subjected domestic chicks (Gallus gallus) to intermittent social isolation, food restriction, and temperature stress for the first three weeks of life. The early life stress resulted in a dampened corticosterone response to restraint stress in the parents and male offspring. Stress-specific genes, such as early growth response 1 (EGR1) and corticotropin releasing hormone receptor 1 (CRHR1), were upregulated when chicks were tested in the context of restraint stress, but not under baseline conditions. Treatment differences in gene expression were also correlated across generations which indicate transgenerational epigenetic inheritance, possibly mediated by differences in maternal yolk estradiol and testosterone. In an associative learning test early stressed birds made more correct choices suggesting a higher coping ability in stressful situations. This study is the first to show transgenerational effects of early life stress in a precocial species by combining behavioural, endocrinological, and transcriptomic measurements.

  • 6.
    Jöngren, Markus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
    Westander, Jennie
    Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
    Nätt, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
    Brain gene expression in relation to fearfulness in female red junglefowl (Gallus gallus)2010In: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 9, no 7, p. 751-758Article in journal (Refereed)
    Abstract [en]

    The biology of fear is central to animal welfare and hasbeen a major target for selection during domestication.Fear responses were studied in female red junglefowl(RJF), the ancestor of domesticated chickens. A totalof 31 females were tested in a ground predator test,an aerial predator test and a tonic immobility (TI)test, in order to assess their level of fearfulnessacross different situations. Two to six variables fromeach test were entered into a principal component(PC) analysis, which showed one major fearfulnesscomponent (explaining 27% of the variance). Based onthe PC scores, four high- and four low-fearful birds werethen selected for gene expression analysis. From eachof these birds, the midbrain region (including thalamus,hypothalamus, pituitary, mesencephalon, pons, nucleustractus solitarii and medulla oblongata), was collectedand global gene expression compared between groupsusing a 14k chicken cDNA microarray. There were 13significantly differentially expressed (DE) genes (basedonM > 1 andB > 0; FDR-adjusted P < 0.05) between thefearful and non-fearful females. Among the DE genes,we identified the neuroprotein Axin1, two potentialDNA/RNA regulating proteins and a retrotransposontranscript situated in a well-studied quantitative traitloci (QTL) region on chromosome 1, known to affectseveral domestication-related traits. The differentiallyexpressed genes may be part of a possible molecularmechanism controlling fear responses in fowl.

  • 7.
    Lindqvist, Christina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
    Janczak, Andrew M.
    Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway.
    Nätt, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
    Baranowska, Izabella
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lindqvist, Niclas
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Wichman, Anette
    Department of Animal Environment and Health, Swedish University of Agricultural Sciences, Skara, Sweden.
    Lundeberg, Joakim
    School of Biotechnology, Department of Gene Technology, Royal Institute of Technology, Stockholm, Sweden.
    Lindberg, Johan
    School of Biotechnology, Department of Gene Technology, Royal Institute of Technology, Stockholm, Sweden.
    Torjesen, Peter A.
    Hormone Laboratory, Aker University Hospital HF, Oslo, Norway.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
    Transmission of Stress-Induced Learning Impairment and Associated Brain Gene Expression from Parents to Offspring in Chickens2007In: PLOS ONE, E-ISSN 1932-6203, Vol. 2, no 4, p. e364-Article in journal (Refereed)
    Abstract [en]

    Background: Stress influences many aspects of animal behaviour and is a major factor driving populations to adapt to changing living conditions, such as during domestication. Stress can affect offspring through non-genetic mechanisms, but recent research indicates that inherited epigenetic modifications of the genome could possibly also be involved.

    Methodology/Principal Findings: Red junglefowl (RJF, ancestors of modern chickens) and domesticated White Leghorn (WL) chickens were raised in a stressful environment (unpredictable light-dark rhythm) and control animals in similar pens, but on a 12/12 h light-dark rhythm. WL in both treatments had poorer spatial learning ability than RJF, and in both populations, stress caused a reduced ability to solve a spatial learning task. Offspring of stressed WL, but not RJF, raised without parental contact, had a reduced spatial learning ability compared to offspring of non-stressed animals in a similar test as that used for their parents. Offspring of stressed WL were also more competitive and grew faster than offspring of non-stressed parents. Using a whole-genome cDNA microarray, we found that in WL, the same changes in hypothalamic gene expression profile caused by stress in the parents were also found in the offspring. In offspring of stressed WL, at least 31 genes were up- or down-regulated in the hypothalamus and pituitary compared to offspring of non-stressed parents.

    Conclusions/ Significance: Our results suggest that, in WL the gene expression response to stress, as well as some behavioural stress responses, were transmitted across generations. The ability to transmit epigenetic information and behaviour modifications between generations may therefore have been favoured by domestication. The mechanisms involved remain to be investigated; epigenetic modifications could either have been inherited or acquired de novo in the specific egg environment. In both cases, this would offer a novel explanation to rapid evolutionary adaptation of a population.

  • 8.
    Mayo, Leah M.
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Asratian, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Lindé, Johan
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Holm, Lovisa
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Nätt, Daniel
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Augier, Gaëlle
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Stensson, Niclas
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Vecchiarelli, Haley A.
    Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Canada.
    Balsevich, Georgia
    Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Canada.
    Aukema, Robert J.
    Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Canada.
    Ghafouri, Bijar
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine.
    Spagnolo, Primavera A.
    National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke, NIH, Bethesda, USA.
    Lee, Francis S.
    Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, USA.
    Hill, Matthew N.
    Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Canada.
    Heilig, Markus
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice2020In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 25, no 5, p. 993-1005Article in journal (Refereed)
    Abstract [en]

    Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C-greater thanA substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.

  • 9. Order onlineBuy this publication >>
    Nätt, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Heritable epigenetic responses to environmental challenges: Effects on behaviour, gene expression and DNA-methylation in the chicken2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Phenotypic variation within populations is a crucial factor in evolution and is mainly thought to be driven by heritable changes in the base sequence of DNA. Among our domesticated species we find some of the most variable species on earth today. This variety of breeds has appeared during a relatively short evolutionary time, and so far genetic studies have been unable to explain but a small portion of this variation, which indicates more novel mechanisms of inheritance and phenotypic plasticity. The aim of this study was therefore to investigate some of these alternative routes in the chicken, especially focusing on transgenerational effects of environmental challenges on behaviour and gene expression in relation to domestication. In two experiments a chronically unpredictable environment induced phenotypic changes in the parents that were mirrored in the unexposed offspring raised without parental contact. This transmission was especially clear in domesticated birds. A third experiment showed that repeated stress events very early in life could change the developmental program making the birds more resistant to stress later in life. Here, the phenotypic changes were also mirrored in the unexposed offspring and associated with inheritance of gene expression. Epigenetic factors, such as DNA-methylation, could play an important role in the mechanism of these transgenerational effects. A fourth experiment showed that wild types and domesticated chickens differed substantially in their patterns of DNA-methylation, where the domesticated breed had increased amount of promoter DNA-methylation. In line with the previous experiments, this breed also showed increased transmission of methylation marks to their  offspring. Conclusively, parental exposure of environmental challenges that introduce changes in behaviour, physiology and gene expression can under both chronic and temporal conditions be heritably programmed in the parent and transmitted to the unexposed offspring. Since heritable epigenetic variation between wild type and domesticated chickens is stable and numerous, it is possible that selection for favourable epigenomes could add another level to the evolutionary processes and therefore might explain some of the rapid changes in the history of the domesticated chicken. 

    List of papers
    1. Transmission of Stress-Induced Learning Impairment and Associated Brain Gene Expression from Parents to Offspring in Chickens
    Open this publication in new window or tab >>Transmission of Stress-Induced Learning Impairment and Associated Brain Gene Expression from Parents to Offspring in Chickens
    Show others...
    2007 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 2, no 4, p. e364-Article in journal (Refereed) Published
    Abstract [en]

    Background: Stress influences many aspects of animal behaviour and is a major factor driving populations to adapt to changing living conditions, such as during domestication. Stress can affect offspring through non-genetic mechanisms, but recent research indicates that inherited epigenetic modifications of the genome could possibly also be involved.

    Methodology/Principal Findings: Red junglefowl (RJF, ancestors of modern chickens) and domesticated White Leghorn (WL) chickens were raised in a stressful environment (unpredictable light-dark rhythm) and control animals in similar pens, but on a 12/12 h light-dark rhythm. WL in both treatments had poorer spatial learning ability than RJF, and in both populations, stress caused a reduced ability to solve a spatial learning task. Offspring of stressed WL, but not RJF, raised without parental contact, had a reduced spatial learning ability compared to offspring of non-stressed animals in a similar test as that used for their parents. Offspring of stressed WL were also more competitive and grew faster than offspring of non-stressed parents. Using a whole-genome cDNA microarray, we found that in WL, the same changes in hypothalamic gene expression profile caused by stress in the parents were also found in the offspring. In offspring of stressed WL, at least 31 genes were up- or down-regulated in the hypothalamus and pituitary compared to offspring of non-stressed parents.

    Conclusions/ Significance: Our results suggest that, in WL the gene expression response to stress, as well as some behavioural stress responses, were transmitted across generations. The ability to transmit epigenetic information and behaviour modifications between generations may therefore have been favoured by domestication. The mechanisms involved remain to be investigated; epigenetic modifications could either have been inherited or acquired de novo in the specific egg environment. In both cases, this would offer a novel explanation to rapid evolutionary adaptation of a population.

    Keywords
    Stress, Prenatal stress, Animal behaviour, Gene expresssion, Domestication, Chicken, Red junglefowl, White Leghorn, Epigenetics, Transgenerational effects, Epigenetic inheritance, Maternal effects, Paternal effects
    Identifiers
    urn:nbn:se:liu:diva-15529 (URN)10.1371/journal.pone.0000364 (DOI)
    Available from: 2008-11-17 Created: 2008-11-14 Last updated: 2023-12-28Bibliographically approved
    2. Inheritance of Acquired Behaviour Adaptions and Brain Gene Expression in Chickens
    Open this publication in new window or tab >>Inheritance of Acquired Behaviour Adaptions and Brain Gene Expression in Chickens
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    2009 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 4, no 7, p. e6405-Article, review/survey (Other academic) Published
    Abstract [en]

    Background: Environmental challenges may affect both the exposed individuals and their offspring. We investigated possible adaptive aspects of such cross-generation transmissions, and hypothesized that chronic unpredictable food access would cause chickens to show a more conservative feeding strategy and to be more dominant, and that these adaptations would be transmitted to the offspring.

    Methodology/Principal Findings: Parents were raised in an unpredictable (UL) or in predictable diurnal light rhythm (PL, 12:12 h light:dark). In a foraging test, UL birds pecked more at freely available, rather than at hidden and more attractive food, compared to birds from the PL group. Female offspring of UL birds, raised in predictable light conditions without parental contact, showed a similar foraging behavior, differing from offspring of PL birds. Furthermore, adult offspring of UL birds performed more food pecks in a dominance test, showed a higher preference for high energy food, survived better, and were heavier than offspring of PL parents. Using cDNA microarrays, we found that the differential brain gene expression caused by the challenge was mirrored in the offspring. In particular, several immunoglobulin genes seemed to be affected similarly in both UL parents and their offspring. Estradiol levels were significantly higher in egg yolk from UL birds, suggesting one possible mechanism for these effects.

    Conclusions/Significance: Our findings suggest that unpredictable food access caused seemingly adaptive responses in feeding behavior, which may have been transmitted to the offspring by means of epigenetic mechanisms, including regulation of immune genes. This may have prepared the offspring for coping with an unpredictable environment.

    Citation: Nätt D, Lindqvist N, Stranneheim H, Lundeberg J, Torjesen PA, et al. (2009) Inheritance of Acquired Behaviour Adaptations and Brain Gene Expression in Chickens. PLoS ONE 4(7): e6405. doi:10.1371/journal.pone.0006405

    Editor: Tom Pizzari, University of Oxford, United Kingdom

    Received: March 26, 2009; Accepted: June 30, 2009; Published: July 28, 2009

    Copyright: © 2009 Nätt et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    Funding: This project was funded by the Swedish Research Council (VR; www.vr.se; grant nrs 50280101 and 50280102) and the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas; www.formas.se; grant no 221-2005-270). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the mauscript.

    Competing interests: The authors have declared that no competing interests exist.

     

    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:liu:diva-19948 (URN)10.1371/journal.pone.0006405 (DOI)
    Note
    Original Publication: Daniel Nätt, Niclas Lindqvist, Henrik Stranneheim, Joakim Lundeberg, Peter A. Torjesen and Per Jensen, Inheritance of Acquired Behaviour Adaptions and Brain Gene Expression in Chickens, 2009, PLoS ONE, (4), 7, e6405. http://dx.doi.org/10.1371/journal.pone.0006405 Copyright: Authors Available from: 2009-08-25 Created: 2009-08-19 Last updated: 2023-12-28Bibliographically approved
    3. Transgenerational effects of early experience on acute stress reactions in behaviour, steroid hormones and gene expression in the precocial chicken
    Open this publication in new window or tab >>Transgenerational effects of early experience on acute stress reactions in behaviour, steroid hormones and gene expression in the precocial chicken
    Show others...
    2012 (English)In: Hormones and Behavior, ISSN 0018-506X, E-ISSN 1095-6867, Vol. 61, no 5, p. 711-718Article in journal (Refereed) Published
    Abstract [en]

    Stress during early life can profoundly influence an individual’s phenotype. Effects can manifest in the short-term as well as later in life and even in subsequent generations. Transgenerational effects of stress are potentially mediated via modulation of the hypothalamic-pituitary-adrenal axis (HPA) as well as epigenetic mechanisms causing heritable changes in gene expression. To investigate these pathways we subjected domestic chicks (Gallus gallus) to intermittent social isolation, food restriction, and temperature stress for the first three weeks of life. The early life stress resulted in a dampened corticosterone response to restraint stress in the parents and male offspring. Stress-specific genes, such as early growth response 1 (EGR1) and corticotropin releasing hormone receptor 1 (CRHR1), were upregulated when chicks were tested in the context of restraint stress, but not under baseline conditions. Treatment differences in gene expression were also correlated across generations which indicate transgenerational epigenetic inheritance, possibly mediated by differences in maternal yolk estradiol and testosterone. In an associative learning test early stressed birds made more correct choices suggesting a higher coping ability in stressful situations. This study is the first to show transgenerational effects of early life stress in a precocial species by combining behavioural, endocrinological, and transcriptomic measurements.

    Keywords
    Early growth response, corticotropin releasing hormone receptor, postnatal stress, behaviour, epigenetics, transgenerational effects, steroid hormones, gene expression
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:liu:diva-70157 (URN)10.1016/j.yhbeh.2012.03.006 (DOI)000304339800007 ()
    Note
    funding agencies|Swedish Research Council||Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning||Available from: 2011-08-22 Created: 2011-08-22 Last updated: 2023-12-28
    4. Heritable genome-wide variation of gene expression and promoter methylation between wild and domesticated chickens
    Open this publication in new window or tab >>Heritable genome-wide variation of gene expression and promoter methylation between wild and domesticated chickens
    Show others...
    2012 (English)In: BMC Genomics, E-ISSN 1471-2164, Vol. 13, no 59Article in journal (Refereed) Published
    Abstract [en]

    Variations in gene expression, mediated by epigenetic mechanisms, may cause broad phenotypic effects in animals. However, it has been debated to what extent expression variation and epigenetic modifications, such as patterns of DNA methylation, are transferred across generations, and therefore it is uncertain what role epigenetic variation may play in adaptation. Here, we show that in Red Junglefowl, ancestor of domestic chickens, gene expression and methylation profiles in thalamus/hypothalamus differ substantially from that of a domesticated egg laying breed. Expression as well as methylation differences are largely maintained in the offspring, demonstrating reliable inheritance of epigenetic variation. Some of the inherited methylation differences are tissue-specific, and the differential methylation at specific loci are little changed after eight generations of intercrossing between Red Junglefowl and domesticated laying hens. There was an over-representation of differentially expressed and methylated genes in selective sweep regions associated with chicken domestication. Hence, our results show that epigenetic variation is inherited in chickens, and we suggest that selection of favourable epigenomes, either by selection of genotypes affecting epigenetic states, or by selection of methylation states which are inherited independently of sequence differences, may have been an important aspect of chicken domestication.

    Place, publisher, year, edition, pages
    BioMed Central, 2012
    Keywords
    Domestication, gene expression, tiling array, behaviour, methylation
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:liu:diva-70159 (URN)10.1186/1471-2164-13-59 (DOI)000301440800001 ()
    Note

    funding agencies|Swedish Research Council| 2008-14496-59340-36 |Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning| 221 2007 838 |

    Available from: 2011-08-22 Created: 2011-08-22 Last updated: 2024-01-17Bibliographically approved
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    Heritable epigenetic responses to environmental challenges
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  • 10. Order onlineBuy this publication >>
    Nätt, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Stress and the Offspring: Adaptive Transgenerational Effects of Unpredictability on Behaviour and Gene Expression in Chickens (Gallus gallus)2008Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Environmental stress has shown to affect both the exposed individuals and the development of their offspring. Generally, it is thought that the stressed organism responds to stress by trying to adapt to it. This thesis investigates possible evolutionary consequences of cross-generational transmissions of stress, where the parent has been stressed but the offspring has not. In two studies we have exposed chicken parents of different breeds to an unpredictable circadian light rhythm, to investigate the influence of genetic background on the transmission of behaviour and patterns of genome-wide gene expression across generations. In Paper I, we can show that the domesticated chicken, by means of epigenetic factors, transmit their behaviours as well as their gene expression profiles to their offspring to a higher extent than their wild ancestor, the red junglefowl. Furthermore, in Paper II, even though the offspring never experienced the stress or had any contact with their stressed parents, they seemed to have adapted to it, which suggests that the parents might have prepared (or pre-adapted) them for living in the unpredictable environment. Additionally, eggs of stressed hens showed increased levels of estradiol that might have affected gene expression of specific immune genes, which were up-regulated in the offspring of stressed parents. It is possible that the traditional distinction between stress responses and evolutionary adaptation may be reevaluated, since our results indicate that they could be parts of the same evolutionary event.

    List of papers
    1. Transmission of Stress-Induced Learning Impairment and Associated Brain Gene Expression from Parents to Offspring in Chickens
    Open this publication in new window or tab >>Transmission of Stress-Induced Learning Impairment and Associated Brain Gene Expression from Parents to Offspring in Chickens
    Show others...
    2007 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 2, no 4, p. e364-Article in journal (Refereed) Published
    Abstract [en]

    Background: Stress influences many aspects of animal behaviour and is a major factor driving populations to adapt to changing living conditions, such as during domestication. Stress can affect offspring through non-genetic mechanisms, but recent research indicates that inherited epigenetic modifications of the genome could possibly also be involved.

    Methodology/Principal Findings: Red junglefowl (RJF, ancestors of modern chickens) and domesticated White Leghorn (WL) chickens were raised in a stressful environment (unpredictable light-dark rhythm) and control animals in similar pens, but on a 12/12 h light-dark rhythm. WL in both treatments had poorer spatial learning ability than RJF, and in both populations, stress caused a reduced ability to solve a spatial learning task. Offspring of stressed WL, but not RJF, raised without parental contact, had a reduced spatial learning ability compared to offspring of non-stressed animals in a similar test as that used for their parents. Offspring of stressed WL were also more competitive and grew faster than offspring of non-stressed parents. Using a whole-genome cDNA microarray, we found that in WL, the same changes in hypothalamic gene expression profile caused by stress in the parents were also found in the offspring. In offspring of stressed WL, at least 31 genes were up- or down-regulated in the hypothalamus and pituitary compared to offspring of non-stressed parents.

    Conclusions/ Significance: Our results suggest that, in WL the gene expression response to stress, as well as some behavioural stress responses, were transmitted across generations. The ability to transmit epigenetic information and behaviour modifications between generations may therefore have been favoured by domestication. The mechanisms involved remain to be investigated; epigenetic modifications could either have been inherited or acquired de novo in the specific egg environment. In both cases, this would offer a novel explanation to rapid evolutionary adaptation of a population.

    Keywords
    Stress, Prenatal stress, Animal behaviour, Gene expresssion, Domestication, Chicken, Red junglefowl, White Leghorn, Epigenetics, Transgenerational effects, Epigenetic inheritance, Maternal effects, Paternal effects
    Identifiers
    urn:nbn:se:liu:diva-15529 (URN)10.1371/journal.pone.0000364 (DOI)
    Available from: 2008-11-17 Created: 2008-11-14 Last updated: 2023-12-28Bibliographically approved
    2. Transgenerational Phenotypic Tuning of Offspring: Adaptive Responses to a Prenatal Environmental Challenge in Chickens
    Open this publication in new window or tab >>Transgenerational Phenotypic Tuning of Offspring: Adaptive Responses to a Prenatal Environmental Challenge in Chickens
    Show others...
    2008 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Stress may affect both the exposed individuals and the development of their offspring. We have previously shown that offspring of stressed domestic chickens can inherit the stressed-induced learning impairments of their parents and the associated modifications in brain gene expression. In this study we investigated possible adaptive aspects of such cross-generation transmissions. We hypothesized that stress would cause chickens to show a more conservative feeding strategy and to be more dominant, and that these adaptations would be transmitted to the offspring. Parents were raised in an unpredictable diurnal light rhythm (stress treatment) or in control conditions (12:12 h light:dark). In a foraging test, stressed birds pecked more at freely available than at hidden and more attractive food compared to birds from the control group. Female offspring of stressed birds, raised in control conditions without parental contact, showed a similar foraging behavior, differing from offspring of control birds. Furthermore, adult offspring of stressed birds performed more food pecks in a dominance test, showed a higher preference for high energy food, survived better, and were heavier than offspring of control parents. One possible explanation for the more dominant behavior of these birds might be increased androgen/estrogen effects from the yolk during their embryonic phase leading to increased anabolism and androgenic behavior. Using cDNA microarrays, we found that some of the differential brain gene expression caused by stress tended to be mirrored in the offspring, indicating transgenerational effects.  In particular, several immunoglobulin genes seemed to be affected similarly in both stressed parents and their offspring. Estradiol, but not corticoserone, testosterone, androstendion, or dihydrotestosterone, was significantly higher in egg yolk from stressed birds, suggesting a possible mechanism for these effects. Our findings suggest that stress may cause adaptive responses in feeding behavior, which may be transmitted to the offspring by means of epigenetic regulation of immune genes. This may in turn prepare the offspring for coping with an unpredictable environment.

    Publisher
    p. 59
    Keywords
    Stress, Prenatal stress, Adaptation, Animal behaviour, Gene expresssion, Microarray, Domestication, Chicken, Epigenetics, Transgenerational effects, Estradiol, Steroid hormones, Epigenetic inheritance, Maternal effects, Paternal effects
    Identifiers
    urn:nbn:se:liu:diva-15530 (URN)978-91-7393-753-5 (ISBN)
    Available from: 2008-11-17 Created: 2008-11-14 Last updated: 2023-12-28Bibliographically approved
    Download full text (pdf)
    FULLTEXT01
  • 11.
    Nätt, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Agnvall, Beatrix
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Large Sex Differences in Chicken Behavior and Brain Gene Expression Coincide with Few Differences in Promoter DNA-Methylation2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 4, p. e96376-Article in journal (Refereed)
    Abstract [en]

    While behavioral sex differences have repeatedly been reported across taxa, the underlying epigenetic mechanisms in thebrain are mostly lacking. Birds have previously shown to have only limited dosage compensation, leading to high sex bias ofZ-chromosome gene expression. In chickens, a male hyper-methylated region (MHM) on the Z-chromosome has beenassociated with a local type of dosage compensation, but a more detailed characterization of the avian methylome islimiting our interpretations. Here we report an analysis of genome wide sex differences in promoter DNA-methylation andgene expression in the brain of three weeks old chickens, and associated sex differences in behavior of Red Junglefowl(ancestor of domestic chickens). Combining DNA-methylation tiling arrays with gene expression microarrays we show that aspecific locus of the MHM region, together with the promoter for the zinc finger RNA binding protein (ZFR) gene onchromosome 1, is strongly associated with sex dimorphism in gene expression. Except for this, we found few differences inpromoter DNA-methylation, even though hundreds of genes were robustly differentially expressed across distantly relatedbreeds. Several of the differentially expressed genes are known to affect behavior, and as suggested from their functionalannotation, we found that female Red Junglefowl are more explorative and fearful in a range of tests performed throughouttheir lives. This paper identifies new sites and, with increased resolution, confirms known sites where DNA-methylationseems to affect sexually dimorphic gene expression, but the general lack of this association is noticeable and strengthensthe view that birds do not have dosage compensation.

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    fulltext
  • 12.
    Nätt, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
    Andersson, Leif
    Department of Animal Breeding and Genetics Uppsala Biomedical Center, Sweden.
    Kerje, Susanne
    Department of Animal Breeding and Genetics Uppsala Biomedical Center, Sweden.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
    Plumage Color and Feather Pecking-Behavioral Differences Associated with PMEL17 Genotypes in Chicken (Gallus gallus)2007In: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 37, no 2, p. 399-407Article in journal (Refereed)
    Abstract [en]

       An F 5 generation of an advanced inter-cross between red junglefowl (wild-type) and White Leghorn (domesticated) was used to investigate earlier findings suggesting that a mutation in the plumage color gene PMEL17 protects against victimization to feather pecking (FP). F 4 parents were selected according to genotype to produce PMEL17 homozygous offspring (i/i and I/I respectively). Birds were raised and their behavior recorded in groups of either two wild-type i/i (dark colored) and one white I/I, or two I/I and one i/i. In addition each bird was tested for feather preference, reaction to novelty, open-field activity, fear for humans, and tonic-immobility. In the home-pens, i/i birds were more feather pecked and had poorer feather condition than I/I birds. No pecking preference for immobile dark colored feathers was observed. In the open-field test i/i birds vocalized more and earlier than I/I birds, and in the fear-for-human test I/I birds had higher activity at 21 weeks of age. No other behavior differences were observed, but clearly, genotypes of PMEL17 affected some aspects of behavior. Such behavioral differences might be important aspects of the mechanism which predispose i/i individuals for being victims of FP.

  • 13.
    Nätt, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Columbia University, NY 10027 USA.
    Barchiesi, Riccardo
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Murad, Josef
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Feng, Jian
    Florida State University, FL 32306 USA; Icahn School Medical Mt Sinai, NY 10029 USA.
    Nestler, Eric J.
    Icahn School Medical Mt Sinai, USA.
    Champagne, Frances A.
    Columbia University, USA.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Perinatal Malnutrition Leads to Sexually Dimorphic Behavioral Responses with Associated Epigenetic Changes in the Mouse Brain2017In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 11082Article in journal (Refereed)
    Abstract [en]

    Childhood malnutrition is a risk factor for mental disorders, such as major depression and anxiety. Evidence shows that similar early life adversities induce sex-dependent epigenetic reprogramming. However, little is known about how genes are specifically affected by early malnutrition and the implications for males and females respectively. One relevant target is neuropeptide Y (NPY), which regulates both stress and food-intake. We studied maternal low protein diet (LPD) during pregnancy/lactation in mice. Male, but not female, offspring of LPD mothers consistently displayed anxiety-and depression-like behaviors under acute stress. Transcriptome-wide analysis of the effects of acute stress in the amygdala, revealed a list of transcription factors affected by either sex or perinatal LPD. Among these immediate early genes (IEG), members of the Early growth response family (Egr1/2/4) were consistently upregulated by perinatal LPD in both sexes. EGR1 also bound the NPY receptor Y1 gene (Npy1r), which co-occurred with sex-specific effects of perinatal LPD on both Npy1r DNA-methylation and gene transcription. Our proposed pathway connecting early malnutrition, sex-independent regulatory changes in Egr1, and sex-specific epigenetic reprogramming of its effector gene, Npy1r, represents the first molecular evidence of how early life risk factors may generate sex-specific epigenetic effects relevant for mental disorders.

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    fulltext
  • 14.
    Nätt, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Johansson, Ingela
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Faresjö, Tomas
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    High cortisol in 5-year-old children causes loss of DNA methylation in SINE retrotransposons: a possible role for ZNF263 in stress-related diseases2015In: Clinical Epigenetics, E-ISSN 1868-7083, ISSN 1868-7083, Vol. 7, no 1, article id 91Article in journal (Refereed)
    Abstract [en]

    Background: Childhood stress leads to increased risk of many adult diseases, such as major depression and cardiovascular disease. Studies show that adults with experienced childhood stress have specific epigenetic changes, but to understand the pathways that lead to disease, we also need to study the epigenetic link prospectively in children. Results: Here, we studied a homogenous group of 48 5-year-old children. By combining hair cortisol measurements (a well-documented biomarker for chronic stress), with whole-genome DNA-methylation sequencing, we show that high cortisol associates with a genome-wide decrease in DNA methylation and targets short interspersed nuclear elements (SINEs; a type of retrotransposon) and genes important for calcium transport: phenomena commonly affected in stress-related diseases and in biological aging. More importantly, we identify a zinc-finger transcription factor, ZNF263, whose binding sites where highly overrepresented in regions experiencing methylation loss. This type of zinc-finger protein has previously shown to be involved in the defense against retrotransposons. Conclusions: Our results show that stress in preschool children leads to changes in DNA methylation similar to those seen in biological aging. We suggest that this may affect future disease susceptibility by alterations in the epigenetic mechanisms that keep retrotransposons dormant. Future treatments for stress-and age-related diseases may therefore seek to target zinc-finger proteins that epigenetically control retrotransposon reactivation, such as ZNF263.

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    fulltext
  • 15.
    Nätt, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
    Lindqvist, Niclas
    Paul-Flechsig-Institute for Brain Research, University of Leipzig, Leipzig, Germany.
    Stranneheim, Henrik
    Royal Institute of Technology, Stockholm.
    Lundeberg, Joakim
    Royal Institute of Technology, Stockholm.
    Torjesen, Peter A.
    Aker University Hospital HF.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
    Inheritance of Acquired Behaviour Adaptions and Brain Gene Expression in Chickens2009In: PLOS ONE, E-ISSN 1932-6203, Vol. 4, no 7, p. e6405-Article, review/survey (Other academic)
    Abstract [en]

    Background: Environmental challenges may affect both the exposed individuals and their offspring. We investigated possible adaptive aspects of such cross-generation transmissions, and hypothesized that chronic unpredictable food access would cause chickens to show a more conservative feeding strategy and to be more dominant, and that these adaptations would be transmitted to the offspring.

    Methodology/Principal Findings: Parents were raised in an unpredictable (UL) or in predictable diurnal light rhythm (PL, 12:12 h light:dark). In a foraging test, UL birds pecked more at freely available, rather than at hidden and more attractive food, compared to birds from the PL group. Female offspring of UL birds, raised in predictable light conditions without parental contact, showed a similar foraging behavior, differing from offspring of PL birds. Furthermore, adult offspring of UL birds performed more food pecks in a dominance test, showed a higher preference for high energy food, survived better, and were heavier than offspring of PL parents. Using cDNA microarrays, we found that the differential brain gene expression caused by the challenge was mirrored in the offspring. In particular, several immunoglobulin genes seemed to be affected similarly in both UL parents and their offspring. Estradiol levels were significantly higher in egg yolk from UL birds, suggesting one possible mechanism for these effects.

    Conclusions/Significance: Our findings suggest that unpredictable food access caused seemingly adaptive responses in feeding behavior, which may have been transmitted to the offspring by means of epigenetic mechanisms, including regulation of immune genes. This may have prepared the offspring for coping with an unpredictable environment.

    Citation: Nätt D, Lindqvist N, Stranneheim H, Lundeberg J, Torjesen PA, et al. (2009) Inheritance of Acquired Behaviour Adaptations and Brain Gene Expression in Chickens. PLoS ONE 4(7): e6405. doi:10.1371/journal.pone.0006405

    Editor: Tom Pizzari, University of Oxford, United Kingdom

    Received: March 26, 2009; Accepted: June 30, 2009; Published: July 28, 2009

    Copyright: © 2009 Nätt et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    Funding: This project was funded by the Swedish Research Council (VR; www.vr.se; grant nrs 50280101 and 50280102) and the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas; www.formas.se; grant no 221-2005-270). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the mauscript.

    Competing interests: The authors have declared that no competing interests exist.

     

    Download full text (pdf)
    FULLTEXT01
  • 16.
    Nätt, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Rubin, Carl-Johan
    Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden.
    Wright, Dominic
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Johnsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Beltéky, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Andersson, Leif
    Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Zoology. Linköping University, The Institute of Technology.
    Heritable genome-wide variation of gene expression and promoter methylation between wild and domesticated chickens2012In: BMC Genomics, E-ISSN 1471-2164, Vol. 13, no 59Article in journal (Refereed)
    Abstract [en]

    Variations in gene expression, mediated by epigenetic mechanisms, may cause broad phenotypic effects in animals. However, it has been debated to what extent expression variation and epigenetic modifications, such as patterns of DNA methylation, are transferred across generations, and therefore it is uncertain what role epigenetic variation may play in adaptation. Here, we show that in Red Junglefowl, ancestor of domestic chickens, gene expression and methylation profiles in thalamus/hypothalamus differ substantially from that of a domesticated egg laying breed. Expression as well as methylation differences are largely maintained in the offspring, demonstrating reliable inheritance of epigenetic variation. Some of the inherited methylation differences are tissue-specific, and the differential methylation at specific loci are little changed after eight generations of intercrossing between Red Junglefowl and domesticated laying hens. There was an over-representation of differentially expressed and methylated genes in selective sweep regions associated with chicken domestication. Hence, our results show that epigenetic variation is inherited in chickens, and we suggest that selection of favourable epigenomes, either by selection of genotypes affecting epigenetic states, or by selection of methylation states which are inherited independently of sequence differences, may have been an important aspect of chicken domestication.

    Download full text (pdf)
    fulltext
  • 17.
    Nätt, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
    Stranneheim, H.
    Lundeberg, Joakim
    School of Biotechnology, Department of Gene Technology, Royal Institute of Technology, Stockholm, Sweden.
    Torjesen, Peter A.
    Hormone Laboratory, Aker University Hospital HF, Oslo, Norway.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Zoology . Linköping University, The Institute of Technology.
    Transgenerational Phenotypic Tuning of Offspring: Adaptive Responses to a Prenatal Environmental Challenge in Chickens2008Manuscript (preprint) (Other academic)
    Abstract [en]

    Stress may affect both the exposed individuals and the development of their offspring. We have previously shown that offspring of stressed domestic chickens can inherit the stressed-induced learning impairments of their parents and the associated modifications in brain gene expression. In this study we investigated possible adaptive aspects of such cross-generation transmissions. We hypothesized that stress would cause chickens to show a more conservative feeding strategy and to be more dominant, and that these adaptations would be transmitted to the offspring. Parents were raised in an unpredictable diurnal light rhythm (stress treatment) or in control conditions (12:12 h light:dark). In a foraging test, stressed birds pecked more at freely available than at hidden and more attractive food compared to birds from the control group. Female offspring of stressed birds, raised in control conditions without parental contact, showed a similar foraging behavior, differing from offspring of control birds. Furthermore, adult offspring of stressed birds performed more food pecks in a dominance test, showed a higher preference for high energy food, survived better, and were heavier than offspring of control parents. One possible explanation for the more dominant behavior of these birds might be increased androgen/estrogen effects from the yolk during their embryonic phase leading to increased anabolism and androgenic behavior. Using cDNA microarrays, we found that some of the differential brain gene expression caused by stress tended to be mirrored in the offspring, indicating transgenerational effects.  In particular, several immunoglobulin genes seemed to be affected similarly in both stressed parents and their offspring. Estradiol, but not corticoserone, testosterone, androstendion, or dihydrotestosterone, was significantly higher in egg yolk from stressed birds, suggesting a possible mechanism for these effects. Our findings suggest that stress may cause adaptive responses in feeding behavior, which may be transmitted to the offspring by means of epigenetic regulation of immune genes. This may in turn prepare the offspring for coping with an unpredictable environment.

  • 18.
    Nätt, Daniel
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology.
    Örtegren Kugelberg, Unn
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology.
    Casas, Eduard
    Josep Carreras Leukaemia Res Inst IJC, Spain.
    Nedstrand, Elizabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Zalavary, Stefan
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Henriksson, Pontus
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Nijm, Carola
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Jaderquist, Julia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Sandborg, Johanna
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Flinke Carlsson, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ramesh, Rashmi
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology.
    Örkenby, Lovisa
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology.
    Appelkvist, Filip
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Lingg, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Guzzi, Nicola
    Lund Univ, Sweden.
    Bellodi, Cristian
    Lund Univ, Sweden.
    Löf, Marie
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Vavouri, Tanya
    Josep Carreras Leukaemia Res Inst IJC, Spain.
    Öst, Anita
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology.
    Human sperm displays rapid responses to diet2019In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 17, no 12, article id e3000559Article in journal (Refereed)
    Abstract [en]

    The global rise in obesity and steady decline in sperm quality are two alarming trends that have emerged during recent decades. In parallel, evidence from model organisms shows that paternal diet can affect offspring metabolic health in a process involving sperm tRNA-derived small RNA (tsRNA). Here, we report that human sperm are acutely sensitive to nutrient flux, both in terms of sperm motility and changes in sperm tsRNA. Over the course of a 2-week diet intervention, in which we first introduced a healthy diet followed by a diet rich in sugar, sperm motility increased and stabilized at high levels. Small RNA-seq on repeatedly sampled sperm from the same individuals revealed that tsRNAs were up-regulated by eating a high-sugar diet for just 1 week. Unsupervised clustering identified two independent pathways for the biogenesis of these tsRNAs: one involving a novel class of fragments with specific cleavage in the T-loop of mature nuclear tRNAs and the other exclusively involving mitochondrial tsRNAs. Mitochondrial involvement was further supported by a similar up-regulation of mitochondrial rRNA-derived small RNA (rsRNA). Notably, the changes in sugar-sensitive tsRNA were positively associated with simultaneous changes in sperm motility and negatively associated with obesity in an independent clinical cohort. This rapid response to a dietary intervention on tsRNA in human sperm is attuned with the paternal intergenerational metabolic responses found in model organisms. More importantly, our findings suggest shared diet-sensitive mechanisms between sperm motility and the biogenesis of tsRNA, which provide novel insights about the interplay between nutrition and male reproductive health.

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  • 19.
    Nätt, Daniel
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Öst, Anita
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Male reproductive health and intergenerational metabolic responses from a small RNA perspective2020In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 288, no 3, p. 305-320Article, review/survey (Refereed)
    Abstract [en]

    The world has recently experienced a decline in male reproductive (e.g. sperm counts and motility) and metabolic (e.g. obesity and diabetes) health. Accumulated evidence from animal models also shows that the metabolic health of the father may influence the metabolic health in his offspring. Vectors for such paternal intergenerational metabolic responses (IGMRs) involve small noncoding RNAs (sncRNAs) that often increase in spermatozoa during the last days of maturation in the epididymis. We and others have shown that the metabolic state - depending on factors such as diet, obesity and physical exercise - may affect sperm quality and sperm sncRNA. Together, this suggests that there are overlapping aetiologies between the male metabolic syndrome, male factor infertility and intergenerational responses. In this review, we present a theoretical framework for an overlap of these aetiologies by exploring the advances in our understanding of the roles of sncRNA in spermatogenesis and offspring development. A special focus will lie on novel findings about tRNA-derived small RNA (tsRNA), rRNA-derived small RNA (rsRNA) and small mitochondrial RNA (mitoRNA), and their emerging roles in intergenerational metabolic and reproductive health.

  • 20.
    Ramesh, Rashmi
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Skog, Signe
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Örkenby, Lovisa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Örtegren Kugelberg, Unn
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Nätt, Daniel
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Öst, Anita
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Dietary Sugar Shifts Mitochondrial Metabolism and Small RNA Biogenesis in Sperm2023In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716Article in journal (Refereed)
    Abstract [en]

    Aims: Increasing concentrations of dietary sugar results in a linear accumulation of triglycerides in male Drosophila, while inducing a U-shaped obesity response in their offspring. Here, using a combination of proteomics and small RNA (sRNA) sequencing, we aimed at understanding the molecular underpinning in sperm for such plasticity.Results: Proteomic analysis of seminal vesicles revealed that increasing concentrations of dietary sugar resulted in a bell-shaped induction of proteins involved in metabolic/redox regulation. Using stains and in vivo redox reporter flies, this pattern could be explained by changes in sperm production of reactive oxygen species (ROS), more exactly mitochondria-derived H2O2. By quenching ROS with the antioxidant N-acetyl cysteine and performing sRNA-seq on sperm, we found that sperm miRNA is increased in response to ROS. Moreover, we found sperm mitosRNA to be increased in high-sugar diet conditions (independent of ROS). Reanalyzing our previously published data revealed a similar global upregulation of human sperm mitosRNA in response to a high-sugar diet, suggesting evolutionary conserved mechanisms.Innovation: This work highlights a fast response to dietary sugar in mitochondria-produced H2O2 in Drosophila sperm and identifies redox-sensitive miRNA downstream of this event.Conclusions: Our data support a model where changes in the sperm mitochondria in response to dietary sugar are the primary event, and changes in redox homoeostasis are secondary to mitochondrial ROS production. These data provide multiple candidates for paternal intergenerational metabolic responses as well as potential biomarkers for human male fertility.

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  • 21.
    Serpeloni, F.
    et al.
    University of Konstanz, Germany.
    Radtke, K.
    University of Konstanz, Germany; University of Konstanz, Germany.
    de Assis, S. G.
    Fundacao Oswaldo Cruz, Brazil.
    Henning, F.
    University of Federal Rio de Janeiro, Brazil.
    Nätt, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Elbert, T.
    University of Konstanz, Germany.
    Grandmaternal stress during pregnancy and DNA methylation of the third generation: an epigenome-wide association study2017In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 7, article id e1202Article in journal (Refereed)
    Abstract [en]

    Stress during pregnancy may impact subsequent generations, which is demonstrated by an increased susceptibility to childhood and adulthood health problems in the children and grandchildren. Although the importance of the prenatal environment is well reported with regards to future physical and emotional outcomes, little is known about the molecular mechanisms that mediate the long-term consequences of early stress across generations. Recent studies have identified DNA methylation as a possible mediator of the impact of prenatal stress in the offspring. Whether psychosocial stress during pregnancy also affects DNA methylation of the grandchildren is still not known. In the present study we examined the multigenerational hypothesis, that is, grandmaternal exposure to psychosocial stress during pregnancy affecting DNA methylation of the grandchildren. We determined the genome-wide DNA methylation profile in 121 children (65 females and 56 males) and tested for associations with exposure to grandmaternal interpersonal violence during pregnancy. We observed methylation variations of five CpG sites significantly (FDR amp;lt; 0.05) associated with the grandmothers report of exposure to violence while pregnant with the mothers of the children. The results revealed differential methylation of genes previously shown to be involved in circulatory system processes (FDRo0.05). This study provides support for DNA methylation as a biological mechanism involved in the transmission of stress across generations and motivates further investigations to examine prenatal-dependent DNA methylation as a potential biomarker for health problems.

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  • 22.
    Serpeloni, Fernanda
    et al.
    Clinical Psychology and Neuropsychology, Department of Psychology, University of Konstanz, Konstanz, Germany; National School of Public Health of Rio de Janeiro and National Institute of Women, Children and Adolescents Health Fernandes Figueira, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
    Nätt, Daniel
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Assis, Simone Gonçalves de
    National School of Public Health of Rio de Janeiro and National Institute of Women, Children and Adolescents Health Fernandes Figueira, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
    Wieling, Elizabeth
    Family Social Science, University of Minnesota, Minneapolis and St. Paul, Minnesota.
    Elbert, Thomas
    Clinical Psychology and Neuropsychology, Department of Psychology, University of Konstanz, Konstanz, Germany.
    Experiencing community and domestic violence is associated with epigenetic changes in DNA methylation of BDNF and CLPX in adolescents2020In: Psychophysiology, ISSN 0048-5772, E-ISSN 1469-8986, Vol. 57, no 1Article in journal (Refereed)
    Abstract [en]

    Experiencing violence changes behavior, shapes personalities, and poses a risk factor for mental disorders. This association might be mediated through epigenetic modifications that affect gene expression, such as DNA methylation. The present study investigated the impact of community and domestic violence on DNA methylation measured in saliva collected from 375 individuals including three generations: grandmothers (n = 126), mothers (n = 125), and adolescents (n = 124, 53% female). Using the Infinium HumanMethylation450 BeadChip array, in adolescents, we detected two CpG sites that showed an association of DNA methylation and lifetime exposure to community and domestic violence even after FDR correction: BDNF_cg06260077 (logFC -0.454, p = 3.71E-07), and CLPX_cg01908660 (logFC = -0.372, p = 1.38E-07). Differential DNA methylation of the CpG BDNF_cg06260077 associated with exposure to violence was also observed in the maternal but not the grandmaternal generation. BDNF (brain-derived neurotrophic factor) and CLPX (caseinolytic mitochondrial matrix peptidase chaperone subunit) genes are involved in neural development. Our results thus reveal altered molecular mechanisms of developmental and intergenerational trajectories in survivors of repeated violent experiences.

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  • 23.
    Serpeloni, Fernanda
    et al.
    Univ Konstanz, Germany; Fundacao Oswaldo Cruz, Brazil.
    Radtke, Karl M.
    Univ Konstanz, Germany; Univ Konstanz, Germany.
    Hecker, Tobias
    Bielefeld Univ, Germany.
    Sill, Johanna
    Univ Konstanz, Germany.
    Vukojevic, Vanja
    Univ Basel, Switzerland.
    de Assis, Simone G.
    Fundacao Oswaldo Cruz, Brazil.
    Schauer, Maggie
    Univ Konstanz, Germany.
    Elbert, Thomas
    Univ Konstanz, Germany.
    Nätt, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Does Prenatal Stress Shape Postnatal Resilience? - An Epigenome-Wide Study on Violence and Mental Health in Humans2019In: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 10, article id 269Article in journal (Refereed)
    Abstract [en]

    Stress during pregnancy widely associates with epigenetic changes and psychiatric problems during childhood. Animal studies, however, show that under specific postnatal conditions prenatal stress may have other, less detrimental consequences for the offspring. Here, we studied mental health and epigenome-wide DNA methylation in saliva following intimate partner violence (IPV) during pregnancy in Sao Goncalo, a Brazilian city with high levels of violence. Not surprisingly, mothers exposed to pregnancy IPV expressed elevated depression, PTSD and anxiety symptoms. Children had similar psychiatric problems when they experienced maternal IPV after being born. More surprisingly, when maternal IPV occurred both during (prenatal) and after pregnancy these problems were absent. Following prenatal IPV, genomic sites in genes encoding the glucocorticoid receptor (NR3C1) and its repressor FKBP51 (FKBP5) were among the most differentially methylated and indicated an enhanced ability to terminate hormonal stress responses in prenatally stressed children. These children also showed more DNA methylation in heterochromatin-like regions, which previously has been associated with stress/disease resilience. A similar relationship was seen in prenatally stressed middle-eastern refugees of the same age as the Sao Goncalo children but exposed to postnatal war-related violence. While our study is limited in location and sample size, it provides novel insights on how prenatal stress may epigenetically shape resilience in humans, possibly through interactions with the postnatal environment. This translates animal findings and emphasizes the importance to account for population differences when studying how early life gene environment interactions affects mental health.

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  • 24.
    Skog, Signe
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Örkenby, Lovisa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Örtegren Kugelberg, Unn
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Öst, Anita
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Nätt, Daniel
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Seqpac: a framework for sRNA-seq analysis in R using sequence-based counts2023In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 39, no 4, article id btad144Article in journal (Refereed)
    Abstract [en]

    Motivation: Feature-based counting is commonly used in RNA-sequencing (RNA-seq) analyses. Here, sequences must align to target features (like genes or non-coding RNAs) and related sequences with different compositions are counted into the same feature. Consequently, sequence integrity is lost, making results less traceable against raw data.Small RNA (sRNA) often maps to multiple features and shows an incredible diversity in form and function. Therefore, applying feature-based strategies may increase the risk of misinterpretation. We present a strategy for sRNA-seq analysis that preserves the integrity of the raw sequence making the data lineage fully traceable. We have consolidated this strategy into Seqpac: An R package that makes a complete sRNA analysis available on multiple platforms. Using published biological data, we show that Seqpac reveals hidden bias and adds new insights to studies that were previously analyzed using feature-based counting.We have identified limitations in the concurrent analysis of RNA-seq data. We call it the traceability dilemma in alignment-based sequencing strategies. By building a flexible framework that preserves the integrity of the read sequence throughout the analysis, we demonstrate better interpretability in sRNA-seq experiments, which are particularly vulnerable to this problem. Applying similar strategies to other transcriptomic workflows may aid in resolving the replication crisis experienced by many fields that depend on transcriptome analyses.

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  • 25.
    Örkenby, Lovisa
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Skog, Signe
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ekman, Helen
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Gozzo, Alessandro
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Örtegren Kugelberg, Unn
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ramesh, Rashmi
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Magadi, Srivathsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Zambanini, Gianluca
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Nordin, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Nätt, Daniel
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Öst, Anita
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Stress-sensitive dynamics of miRNAs and Elba1 in Drosophila embryogenesis2023In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 19, no 5, article id e11148Article in journal (Refereed)
    Abstract [en]

    Early-life stress can result in life-long effects that impact adult health and disease risk, but little is known about how such programming is established and maintained. Here, we show that such epigenetic memories can be initiated in the Drosophila embryo before the major wave of zygotic transcription, and higher-order chromatin structures are established. An early short heat shock results in elevated levels of maternal miRNA and reduced levels of a subgroup of zygotic genes in stage 5 embryos. Using a Dicer-1 mutant, we show that the stress-induced decrease in one of these genes, the insulator-binding factor Elba1, is dependent on functional miRNA biogenesis. Reduction in Elba1 correlates with the upregulation of early developmental genes and promotes a sustained weakening of heterochromatin in the adult fly as indicated by an increased expression of the PEV w(m4h) reporter. We propose that maternal miRNAs, retained in response to an early embryonic heat shock, shape the subsequent de novo heterochromatin establishment that occurs during early development via direct or indirect regulation of some of the earliest expressed genes, including Elba1.

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  • 26.
    Örtegren Kugelberg, Unn
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Nätt, Daniel
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Skog, Signe
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Kutter, Claudia
    Karolinska Inst, Sweden.
    Öst, Anita
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    5 XP sRNA-seq: efficient identification of transcripts with and without 5 phosphorylation reveals evolutionary conserved small RNA2021In: RNA Biology, ISSN 1547-6286, E-ISSN 1555-8584, Vol. 18, no 11, p. 1588-1599Article in journal (Refereed)
    Abstract [en]

    Small RNA (sRNA) sequencing has been critical for our understanding of many cellular processes, including gene regulation. Nonetheless, the varying biochemical properties of sRNA, such as 5 nucleotide modifications, make many sRNA subspecies incompatible with common protocols for sRNA sequencing. Here we describe 5XP-seq that outlines a novel strategy that captures a more complete picture of sRNA. By tagging 5 P sRNA during library preparation, 5XP-seq combines an open approach that includes all types of 5MODIFIER LETTER PRIME-terminal modifications (5 X), with a selective approach for 5-phosphorylated sRNA (5 P). We show that 5XP-seq not only enriches phosphorylated miRNA and piRNA but successfully discriminates these sRNA from all other sRNA species. We further demonstrate the importance of this strategy by successful inter-species validation of sRNAs that would have otherwise failed, including human to insect translation of several tRNA (tRFs) and rRNA (rRFs) fragments. By combining 5 insensitive library strategies with 5 sensitive tagging, we have successfully tackled an intrinsic bias in modern sRNA sequencing that will help us reveal the true complexity and the evolutionary significance of the sRNA world.

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