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  • 1.
    Bivik, Caroline
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Macdonald, Ryan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. University of Cambridge, England.
    Gunnar, Erika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Mazouni, Khalil
    Institute Pasteur, France; CNRS, France.
    Schweisguth, Francois
    Institute Pasteur, France; CNRS, France.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 4, article id e1005984Article in journal (Refereed)
    Abstract [en]

    The Notch pathway controls proliferation during development and in adulthood, and is frequently affected in many disorders. However, the genetic sensitivity and multi-layered transcriptional properties of the Notch pathway has made its molecular decoding challenging. Here, we address the complexity of Notch signaling with respect to proliferation, using the developing Drosophila CNS as model. We find that a Notch/Su(H)/E(spl)-HLH cascade specifically controls daughter, but not progenitor proliferation. Additionally, we find that different E(spl)-HLH genes are required in different neuroblast lineages. The Notch/Su(H)/E(spl)-HLH cascade alters daughter proliferation by regulating four key cell cycle factors: Cyclin E, String/Cdc25, E2f and Dacapo (mammalian p21(CIP1)/p27(KIP1)/p57(Kip2)). ChIP and DamID analysis of Su(H) and E(spl)-HLH indicates direct transcriptional regulation of the cell cycle genes, and of the Notch pathway itself. These results point to a multi-level signaling model and may help shed light on the dichotomous proliferative role of Notch signaling in many other systems.

  • 2.
    Fernius, Josefin
    et al.
    Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, United Kingdom.
    Hardwick, Kevin G.
    Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, United Kingdom.
    Bub1 kinase targets Sgo1 to ensure efficient chromosome biorientation in budding yeast mitosis.2007In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 3, no 11, article id e213Article in journal (Refereed)
    Abstract [en]

    During cell division all chromosomes must be segregated accurately to each daughter cell. Errors in this process give rise to aneuploidy, which leads to birth defects and is implicated in cancer progression. The spindle checkpoint is a surveillance mechanism that ensures high fidelity of chromosome segregation by inhibiting anaphase until all kinetochores have established bipolar attachments to spindle microtubules. Bub1 kinase is a core component of the spindle checkpoint, and cells lacking Bub1 fail to arrest in response to microtubule drugs and precociously segregate their DNA. The mitotic role(s) of Bub1 kinase activity remain elusive, and it is controversial whether this C-terminal domain of Bub1p is required for spindle checkpoint arrest. Here we make a detailed analysis of budding yeast cells lacking the kinase domain (bub1DeltaK). We show that despite being able to arrest in response to microtubule depolymerisation and kinetochore-microtubule attachment defects, bub1DeltaK cells are sensitive to microtubule drugs. This is because bub1DeltaK cells display significant chromosome mis-segregation upon release from nocodazole arrest. bub1DeltaK cells mislocalise Sgo1p, and we demonstrate that both the Bub1 kinase domain and Sgo1p are required for accurate chromosome biorientation after nocodazole treatment. We propose that Bub1 kinase and Sgo1p act together to ensure efficient biorientation of sister chromatids during mitosis.

  • 3.
    Fernius, Josefin
    et al.
    The Wellcome Trust Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, United Kingdom.
    Marston, Adele L.
    The Wellcome Trust Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, United Kingdom.
    Establishment of cohesion at the pericentromere by the Ctf19 kinetochore subcomplex and the replication fork-associated factor, Csm32009In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 5, no 9, article id e1000629Article in journal (Refereed)
    Abstract [en]

    The cohesin complex holds sister chromatids together from the time of their duplication in S phase until their separation during mitosis. Although cohesin is found along the length of chromosomes, it is most abundant at the centromere and surrounding region, the pericentromere. We show here that the budding yeast Ctf19 kinetochore subcomplex and the replication fork-associated factor, Csm3, are both important mediators of pericentromeric cohesion, but they act through distinct mechanisms. We show that components of the Ctf19 complex direct the increased association of cohesin with the pericentromere. In contrast, Csm3 is dispensable for cohesin enrichment in the pericentromere but is essential in ensuring its functionality in holding sister centromeres together. Consistently, cells lacking Csm3 show additive cohesion defects in combination with mutants in the Ctf19 complex. Furthermore, delaying DNA replication rescues the cohesion defect observed in cells lacking Ctf19 complex components, but not Csm3. We propose that the Ctf19 complex ensures additional loading of cohesin at centromeres prior to passage of the replication fork, thereby ensuring its incorporation into functional linkages through a process requiring Csm3.

  • 4.
    Li, He
    et al.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; University of Calif San Diego, CA 92093 USA.
    Ragna Reksten, Tove
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Bergen, Norway.
    Ice, John A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Adrianto, Indra
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Rasmussen, Astrid
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Wang, Shaofeng
    Oklahoma Medical Research Fdn, OK 73104 USA.
    He, Bo
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Grundahl, Kiely M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Glenn, Stuart B.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Miceli-Richard, Corinne
    University of Paris Sud, France.
    Bowman, Simon
    University Hospital Birmingham, England.
    Lester, Sue
    Queen Elizabeth Hospital, Australia.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Eloranta, Maija-Leena
    Uppsala University, Sweden.
    Brun, Johan G.
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Goransson, Lasse G.
    Stavanger University Hospital, Norway.
    Harboe, Erna
    Stavanger University Hospital, Norway.
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; US Department Vet Affairs, OH USA.
    Kvarnstrom, Marika
    Karolinska Institute, Sweden.
    Cunninghame Graham, Deborah S.
    Kings Coll London, England.
    Patel, Ketan
    University of Minnesota, MN 55455 USA; North Mem Medical Centre, MN USA.
    Adler, Adam J.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Darise Farris, A.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Brennan, Michael T.
    Carolinas Medical Centre, NC 28203 USA.
    Chodosh, James
    Harvard Medical Sch, MA USA.
    Gopalakrishnan, Rajaram
    University of Minnesota, MN 55455 USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Venuturupalli, Swamy
    Cedars Sinai Medical Centre, CA 90048 USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Hefner, Kimberly S.
    Cedars Sinai Medical Centre, CA 90048 USA; Hefner Eye Care and Opt Centre, OK USA.
    Houston, Glen D.
    University of Oklahoma, OK USA; Heartland Pathol Consultants, OK USA.
    Huang, Andrew J. W.
    Washington University, MO 63130 USA.
    Hughes, Pamela J.
    University of Minnesota, MN 55455 USA.
    Lewis, David M.
    University of Oklahoma, OK USA.
    Radfar, Lida
    University of Oklahoma, OK USA.
    Vista, Evan S.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Santo Tomas Hospital, Philippines.
    Edgar, Contessa E.
    Oklahoma Baptist University, OK USA.
    Rohrer, Michael D.
    University of Minnesota, MN 55455 USA.
    Stone, Donald U.
    Johns Hopkins University, MD USA.
    Vyse, Timothy J.
    Kings Coll London, England.
    Harley, John B.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; US Department Vet Affairs, OH USA.
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    James, Judith A.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; University of Oklahoma, OK USA.
    Turner, Sean
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Alevizos, Ilias
    National Institute Dent and Craniofacial Research, MD USA.
    Anaya, Juan-Manuel
    University of Rosario, Colombia.
    Rhodus, Nelson L.
    University of Minnesota, MN 55455 USA.
    Segal, Barbara M.
    University of Minnesota, MN 55455 USA.
    Montgomery, Courtney G.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Hal Scofield, R.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; US Department Vet Affairs, OK USA.
    Kovats, Susan
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Mariette, Xavier
    University of Paris Sud, France.
    Ronnblom, Lars
    Uppsala University, Sweden.
    Witte, Torsten
    Hannover Medical Sch, Germany.
    Rischmueller, Maureen
    Queen Elizabeth Hospital, Australia; University of Adelaide, Australia.
    Wahren-Herlenius, Marie
    Karolinska Institute, Sweden.
    Omdal, Roald
    Stavanger University Hospital, Norway.
    Jonsson, Roland
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Ng, Wan-Fai
    Newcastle University, England; Newcastle University, England.
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Lessard, Christopher J.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Identification of a Sjögrens syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 6, article id e1006820Article in journal (Refereed)
    Abstract [en]

    Sjogrens syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2-5-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 x 10(-14)). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (P-meta = 2.59 x 10(-9); odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3 end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.

  • 5.
    Monedero, Ignacio
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Autonoma Madrid, Spain.
    Bivik, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Li, Jin
    Texas AandM Univ, TX USA; Texas AandM Univ, TX USA.
    Yu, Peng
    Texas AandM Univ, TX USA.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Benito-Sipos, Jonathan
    Univ Autonoma Madrid, Spain.
    Specification of Drosophila neuropeptidergic neurons by the splicing component brr22018In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 8, article id e1007496Article in journal (Refereed)
    Abstract [en]

    During embryonic development, a number of genetic cues act to generate neuronal diversity. While intrinsic transcriptional cascades are well-known to control neuronal sub-type cell fate, the target cells can also provide critical input to specific neuronal cell fates. Such signals, denoted retrograde signals, are known to provide critical survival cues for neurons, but have also been found to trigger terminal differentiation of neurons. One salient example of such target-derived instructive signals pertains to the specification of the Drosophila FMRFamide neuropeptide neurons, the Tv4 neurons of the ventral nerve cord. Tv4 neurons receive a BMP signal from their target cells, which acts as the final trigger to activate the FMRFa gene. A recent FMRFa-eGFP genetic screen identified several genes involved in Tv4 specification, two of which encode components of the U5 subunit of the spliceosome: brr2 (l(3) 72Ab) and Prp8. In this study, we focus on the role of RNA processing during target- derived signaling. We found that brr2 and Prp8 play crucial roles in controlling the expression of the FMRFa neuropeptide specifically in six neurons of the VNC (Tv4 neurons). Detailed analysis of brr2 revealed that this control is executed by two independent mechanisms, both of which are required for the activation of the BMP retrograde signaling pathway in Tv4 neurons: (1) Proper axonal pathfinding to the target tissue in order to receive the BMP ligand. (2) Proper RNA splicing of two genes in the BMP pathway: the thickveins (tkv) gene, encoding a BMP receptor subunit, and the Medea gene, encoding a co-Smad. These results reveal involvement of specific RNA processing in diversifying neuronal identity within the central nervous system.

  • 6.
    Nazaryan-Petersen, Lusine
    et al.
    Univ Copenhagen, Denmark.
    Eisfeldt, Jesper
    Karolinska Inst, Sweden; Karolinska Inst Sci Pk, Sweden.
    Pettersson, Maria
    Karolinska Inst, Sweden.
    Lundin, Johanna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Nilsson, Daniel
    Karolinska Inst, Sweden; Karolinska Inst Sci Pk, Sweden; Karolinska Univ Hosp, Sweden.
    Wincent, Josephine
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Lieden, Agne
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Lovmar, Lovisa
    Sahlgrens Univ Hosp, Sweden.
    Ottosson, Jesper
    Sahlgrens Univ Hosp, Sweden.
    Gacic, Jelena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Makitie, Outi
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Univ Helsinki, Finland; Helsinki Univ Hosp, Finland; Folkhalsan Inst Genet, Finland.
    Nordgren, Ann
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Vezzi, Francesco
    Stockholm Univ, Sweden; Devyser AB, Sweden.
    Wirta, Valtteri
    KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Kaller, Max
    KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Hjortshoj, Tina Duelund
    Rigshosp, Denmark.
    Jespersgaard, Cathrine
    Rigshosp, Denmark.
    Houssari, Rayan
    Rigshosp, Denmark.
    Pignata, Laura
    Rigshosp, Denmark.
    Bak, Mads
    Univ Copenhagen, Denmark.
    Tommerup, Niels
    Univ Copenhagen, Denmark.
    Lundberg, Elisabeth Syk
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Tumer, Zeynep
    Rigshosp, Denmark; Univ Copenhagen, Denmark.
    Lindstrand, Anna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization2018In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 11, article id e1007780Article in journal (Refereed)
    Abstract [en]

    Clustered copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) are often reported as germline chromothripsis. However, such cases might need further investigations by massive parallel whole genome sequencing (WGS) in order to accurately define the underlying complex rearrangement, predict the occurrence mechanisms and identify additional complexities. Here, we utilized WGS to delineate the rearrangement structure of 21 clustered CNV carriers first investigated by CMA and identified a total of 83 breakpoint junctions (BPJs). The rearrangements were further sub-classified depending on the patterns observed: I) Cases with only deletions (n = 8) often had additional structural rearrangements, such as insertions and inversions typical to chromothripsis; II) cases with only duplications (n = 7) or III) combinations of deletions and duplications (n = 6) demonstrated mostly interspersed duplications and BPJs enriched with microhomology. In two cases the rearrangement mutational signatures indicated both a breakage-fusion-bridge cycle process and haltered formation of a ring chromosome. Finally, we observed two cases with Alu- and LINE-mediated rearrangements as well as two unrelated individuals with seemingly identical clustered CNVs on 2p25.3, possibly a rare European founder rearrangement. In conclusion, through detailed characterization of the derivative chromosomes we show that multiple mechanisms are likely involved in the formation of clustered CNVs and add further evidence for chromoanagenesis mechanisms in both "simple" and highly complex chromosomal rearrangements. Finally, WGS characterization adds positional information, important for a correct clinical interpretation and deciphering mechanisms involved in the formation of these rearrangements.

  • 7.
    Nestor, Colm
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Barrenäs, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Wang, Hui
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Lentini, Antonio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Bruhn, Sören
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Jornsten, Rebecka
    University of Gothenburg, Sweden .
    Langston, Michael A.
    University of Tennessee, TN USA .
    Rogers, Gary
    University of Tennessee, TN USA .
    Gustafsson, Mika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    DNA Methylation Changes Separate Allergic Patients from Healthy Controls and May Reflect Altered CD4(+) T-Cell Population Structure2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 1, p. e1004059-Article in journal (Refereed)
    Abstract [en]

    Altered DNA methylation patterns in CD4(+) T-cells indicate the importance of epigenetic mechanisms in inflammatory diseases. However, the identification of these alterations is complicated by the heterogeneity of most inflammatory diseases. Seasonal allergic rhinitis (SAR) is an optimal disease model for the study of DNA methylation because of its welldefined phenotype and etiology. We generated genome-wide DNA methylation (N-patients = 8, N-controls = 8) and gene expression (N-patients = 9, N-controls = 10) profiles of CD4(+) T-cells from SAR patients and healthy controls using Illuminas HumanMethylation450 and HT-12 microarrays, respectively. DNA methylation profiles clearly and robustly distinguished SAR patients from controls, during and outside the pollen season. In agreement with previously published studies, gene expression profiles of the same samples failed to separate patients and controls. Separation by methylation (N-patients = 12, N-controls = 12), but not by gene expression (N-patients = 21, N-controls = 21) was also observed in an in vitro model system in which purified PBMCs from patients and healthy controls were challenged with allergen. We observed changes in the proportions of memory T-cell populations between patients (N-patients = 35) and controls (N-controls = 12), which could explain the observed difference in DNA methylation. Our data highlight the potential of epigenomics in the stratification of immune disease and represents the first successful molecular classification of SAR using CD4(+) T cells.

  • 8.
    Okuyama, Kazuki
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden.
    Kuruvilla, Jacob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden.
    Somasundaram, Rajesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Smith, Emma
    Lund Univ, Sweden.
    Prasad, Mahadesh
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Fioretos, Thoas
    Lund Univ, Sweden.
    Lilljebjorn, Henrik
    Lund Univ, Sweden.
    Soneji, Shamit
    Lund Univ, Sweden.
    Lang, Stefan
    Lund Univ, Sweden.
    Ungerback, Jonas
    Lund Univ, Sweden.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden.
    PAX5 is part of a functional transcription factor network targeted in lymphoid leukemia2019In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 15, no 8, article id e1008280Article in journal (Refereed)
    Abstract [en]

    One of the most frequently mutated proteins in human B-lineage leukemia is the transcription factor PAX5. These mutations often result in partial rather than complete loss of function of the transcription factor. While the functional dose of PAX5 has a clear connection to human malignancy, there is limited evidence for that heterozygote loss of PAX5 have a dramatic effect on the development and function of B-cell progenitors. One possible explanation comes from the finding that PAX5 mutated B-ALL often display complex karyotypes and additional mutations. Thus, PAX5 might be one component of a larger transcription factor network targeted in B-ALL. To investigate the functional network associated with PAX5 we used BioID technology to isolate proteins associated with this transcription factor in the living cell. This identified 239 proteins out of which several could be found mutated in human B-ALL. Most prominently we identified the commonly mutated IKZF1 and RUNX1, involved in the formation of ETV6-AML1 fusion protein, among the interaction partners. ChIP- as well as PLAC-seq analysis supported the idea that these factors share a multitude of target genes in human B-ALL cells. Gene expression analysis of mouse models and primary human leukemia suggested that reduced function of PAX5 increased the ability of an oncogenic form of IKZF1 or ETV6-AML to modulate gene expression. Our data reveals that PAX5 belong to a regulatory network frequently targeted by multiple mutations in B-ALL shedding light on the molecular interplay in leukemia cells. Author summary The use of modern high throughput DNA-sequencing has dramatically increased our ability to identify genetic alterations associated with cancer. However, while the mutations per se are rather easily identified, our understanding of how these mutations impact cellular functions and drive malignant transformation is more limited. We have explored the function of the transcription factor PAX5, commonly mutated in human B-lymphocyte leukemia, to identify a regulatory network of transcription factors often targeted in human disease. Hence, we propose that malignant conversion of B-lymphocyte progenitors involves multiple targeting of a central transcription factor network aggravating the impact of the individual mutations. These data increase our understanding for how individual mutations collaborate to drive the formation of B-lineage leukemia.

  • 9.
    Schwochow Thalmann, Doreen
    et al.
    Swedish University of Agriculture Science, Sweden; University of Paris Saclay, France.
    Ring, Henrik
    Uppsala University, Sweden.
    Sundstrom, Elisabeth
    Uppsala University, Sweden.
    Cao, Xiaofang
    Uppsala University, Sweden.
    Larsson, Marten
    Uppsala University, Sweden.
    Kerje, Susanne
    Uppsala University, Sweden.
    Höglund, Andrey
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Fogelholm, Jesper
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Wright, Dominic
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Jemth, Per
    Uppsala University, Sweden.
    Hallbook, Finn
    Uppsala University, Sweden.
    BedHom, Bertrand
    University of Paris Saclay, France.
    Dorshorst, Ben
    Virginia Tech, VA USA.
    Tixier-Boichard, Michele
    University of Paris Saclay, France.
    Andersson, Leif
    Swedish University of Agriculture Science, Sweden; Uppsala University, Sweden; Texas AandM University, TX 77843 USA.
    The evolution of Sex-linked barring alleles in chickens involves both regulatory and coding changes in CDKN2A2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006665Article in journal (Refereed)
    Abstract [en]

    Sex-linked barring is a fascinating plumage pattern in chickens recently shown to be associated with two non-coding and two missense mutations affecting the ARF transcript at the CDKN2A tumor suppressor locus. It however remained a mystery whether all four mutations are indeed causative and how they contribute to the barring phenotype. Here, we show that Sex-linked barring is genetically heterogeneous, and that the mutations form three functionally different variant alleles. The B0 allele carries only the two non-coding changes and is associated with the most dilute barring pattern, whereas the B1 and B2 alleles carry both the two non-coding changes and one each of the two missense mutations causing the Sex-linked barring and Sex-linked dilution phenotypes, respectively. The data are consistent with evolution of alleles where the non-coding changes occurred first followed by the two missense mutations that resulted in a phenotype more appealing to humans. We show that one or both of the non-coding changes are cis-regulatory mutations causing a higher CDKN2A expression, whereas the missense mutations reduce the ability of ARF to interact with MDM2. Caspase assays for all genotypes revealed no apoptotic events and our results are consistent with a recent study indicating that the loss of melanocyte progenitors in Sex-linked barring in chicken is caused by premature differentiation and not apoptosis. Our results show that CDKN2A is a major locus driving the differentiation of avian melanocytes in a temporal and spatial manner.

  • 10.
    Stocks, Michael
    et al.
    University of Sheffield, Sheffield, United Kingdom; Department of Plant Ecology and Evolution, Uppsala University, Uppsala, Sweden.
    Dean, Rebecca
    Uppsala University, Uppsala, Sweden; Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
    Rogell, Björn
    Department of Animal Ecology, Uppsala University, Uppsala, Sweden; Department of Zoology, Stockholm University, Stockholm, Sweden.
    Friberg, Urban
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology. Department of Evolutionary Biology, Uppsala University, Uppsala, Sweden.
    Sex-specific Trans-regulatory Variation on the Drosophila melanogaster X Chromosome2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 2, p. 1-19, article id e1005015Article in journal (Refereed)
    Abstract [en]

    The X chromosome constitutes a unique genomic environment because it is present in onecopy in males, but two copies in females. This simple fact has motivated several theoreticalpredictions with respect to how standing genetic variation on the X chromosome should differfrom the autosomes. Unmasked expression of deleterious mutations in males and alower census size are expected to reduce variation, while allelic variants with sexually antagonisticeffects, and potentially those with a sex-specific effect, could accumulate on theX chromosome and contribute to increased genetic variation. In addition, incomplete dosagecompensation of the X chromosome could potentially dampen the male-specific effectsof random mutations, and promote the accumulation of X-linked alleles with sexually dimorphicphenotypic effects. Here we test both the amount and the type of genetic variation onthe X chromosome within a population of Drosophila melanogaster, by comparing the proportionof X linked and autosomal trans-regulatory SNPs with a sexually concordant anddiscordant effect on gene expression. We find that the X chromosome is depleted for SNPswith a sexually concordant effect, but hosts comparatively more SNPs with a sexually discordanteffect. Interestingly, the contrasting results for SNPs with sexually concordant anddiscordant effects are driven by SNPs with a larger influence on expression in females thanexpression in males. Furthermore, the distribution of these SNPs is shifted towards regionswhere dosage compensation is predicted to be less complete. These results suggest thatintrinsic properties of dosage compensation influence either the accumulation of differenttypes of trans-factors and/or their propensity to accumulate mutations. Our findings documenta potential mechanistic basis for sex-specific genetic variation, and identify the X as areservoir for sexually dimorphic phenotypic variation. These results have general implicationsfor X chromosome evolution, as well as the genetic basis of sex-specificevolutionary change.

  • 11.
    Stratmann, Johannes
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Neuronal cell fate specification by the molecular convergence of different spatio-temporal cues on a common initiator terminal selector gene2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, p. 26Article in journal (Refereed)
    Abstract [en]

    The extensive genetic regulatory flows underlying specification of different neuronal subtypes are not well understood at the molecular level. The Nplp1 neuropeptide neurons in the developing Drosophila nerve cord belong to two sub-classes; Tv1 and dAp neurons, generated by two distinct progenitors. Nplp1 neurons are specified by spatial cues; the Hox homeotic network and GATA factor grn, and temporal cues; the hb -greater than Kr -greater than Pdm -greater than cas -greater than grh temporal cascade. These spatio-temporal cues combine into two distinct codes; one for Tv1 and one for dAp neurons that activate a common terminal selector feedforward cascade of col -greater than ap/eya -greater than dimm -greater than Nplp1. Here, we molecularly decode the specification of Nplp1 neurons, and find that the cis-regulatory organization of col functions as an integratory node for the different spatio-temporal combinatorial codes. These findings may provide a logical framework for addressing spatio-temporal control of neuronal sub-type specification in other systems. [ABSTRACT FROM AUTHOR]

  • 12.
    Velicky, Philipp
    et al.
    Med Univ Vienna, Austria; IST Austria, Austria.
    Meinhardt, Gudrun
    Med Univ Vienna, Austria.
    Plessl, Kerstin
    Med Univ Vienna, Austria; Univ Appl Sci, Austria.
    Vondra, Sigrid
    Med Univ Vienna, Austria.
    Weiss, Tamara
    St Anna Childrens Hosp, Austria; Med Univ Vienna, Austria.
    Haslinger, Peter
    Med Univ Vienna, Austria.
    Lendl, Thomas
    Inst Mol Biotechnol, Austria; Gregor Mendel Inst, Austria.
    Aumayr, Karin
    Inst Mol Biotechnol, Austria; Gregor Mendel Inst, Austria.
    Mairhofer, Mario
    Med Univ Vienna, Austria; Univ Appl Sci Upper Austria, Austria.
    Zhu, Xiaowei
    Stanford Univ, CA 94305 USA.
    Schuetz, Birgit
    Med Univ Vienna, Austria.
    Hannibal, Roberta L.
    Stanford Univ, CA USA; Second Genome, CA USA.
    Lindau, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Weil, Beatrix
    Med Univ Vienna, Austria.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Neesen, Juergen
    Med Univ Vienna, Austria.
    Egger, Gerda
    Med Univ Vienna, Austria.
    Mikula, Mario
    Med Univ Vienna, Austria.
    Roehrl, Clemens
    Med Univ Vienna, Austria.
    Urban, Alexander E.
    Stanford Univ, CA USA.
    Baker, Julie
    Stanford Univ, CA USA.
    Knoefler, Martin
    Med Univ Vienna, Austria.
    Pollheimer, Juergen
    Med Univ Vienna, Austria.
    Genome amplification and cellular senescence are hallmarks of human placenta development2018In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 10, article id e1007698Article in journal (Refereed)
    Abstract [en]

    Genome amplification and cellular senescence are commonly associated with pathological processes. While physiological roles for polyploidization and senescence have been described in mouse development, controversy exists over their significance in humans. Here, we describe tetraploidization and senescence as phenomena of normal human placenta development. During pregnancy, placental extravillous trophoblasts (EVTs) invade the pregnant endometrium, termed decidua, to establish an adapted microenvironment required for the developing embryo. This process is critically dependent on continuous cell proliferation and differentiation, which is thought to follow the classical model of cell cycle arrest prior to terminal differentiation. Strikingly, flow cytometry and DNAseq revealed that EVT formation is accompanied with a genome-wide polyploidization, independent of mitotic cycles. DNA replication in these cells was analysed by a fluorescent cell-cycle indicator reporter system, cell cycle marker expression and EdU incorporation. Upon invasion into the decidua, EVTs widely lose their replicative potential and enter a senescent state characterized by high senescence-associated (SA) beta-galactosidase activity, induction of a SA secretory phenotype as well as typical metabolic alterations. Furthermore, we show that the shift from endocycle-dependent genome amplification to growth arrest is disturbed in androgenic complete hydatidiform moles (CHM), a hyperplastic pregnancy disorder associated with increased risk of developing choriocarinoma. Senescence is decreased in CHM-EVTs, accompanied by exacerbated endoreduplication and hyperploidy. We propose induction of cellular senescence as a ploidy-limiting mechanism during normal human placentation and unravel a link between excessive polyploidization and reduced senescence in CHM.

  • 13.
    von Salome, Jenny
    et al.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Boonstra, Philip S.
    University of Michigan, MI 48109 USA.
    Karimi, Masoud
    Karolinska University Hospital, Sweden.
    Silander, Gustav
    Umeå University, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics. Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.
    Gebre-Medhin, Samuel
    Off Medical Serv, Sweden; Lund University, Sweden.
    Aravidis, Christos
    Uppsala University, Sweden.
    Nilbert, Mef
    Lund University, Sweden; University of Copenhagen, Denmark.
    Lindblom, Annika
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Lagerstedt-Robinson, Kristina
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Genetic anticipation in Swedish Lynch syndrome families2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 10, article id e1007012Article in journal (Refereed)
    Abstract [en]

    Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a large cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linkoping, Uppsala and Umea between the years 1990-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are smaller.

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