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  • 1.
    Gréen, Anna
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Histone H1: Subtypes and phosphorylation in cell life and death2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The genetic information of a human diploid cell is contained within approximately 2 metres of linear DNA. The DNA molecules are compacted and organized in various ways to fit inside the cell nucleus. Various kinds of histones are involved in this compaction. One of these histones, histone H1 is the topic of the present thesis. In addition to its structural role, H1 histones have been implicated in various processes, for example gene regulation and inhibition of chromatin replication.

    H1 histones, also termed linker histones, are relatively conserved proteins, and the various subtypes seem to have different and important functions even though redundancy between the subtypes has been demonstrated. Despite the sequence conservation of H1 subtypes, two sequence variations were detected within the H1.2 and H1.4 subtypes using hydrophilic interaction liquid chromatographic separation of H1 proteins from K562 and Raji cell lines in Paper I in the present thesis. The variations were confirmed by genetic analysis, and the H1.2 sequence variation was also found in genomic DNA of normal blood donors, in an allele frequency of 6.8%. The H1.4 sequence variation was concluded to be Raji specific. The significance of H1 microsequence variants is unclear, since the physiological function of H1 histones remains to be established.

    H1 histones can be phosphorylated at multiple sites. Changes in H1 phosphorylation has been detected in apoptosis, the cell cycle, gene regulation, mitotic chromatin condensation and malignant transformation. Contradictory data have been obtained on H1 phosphorylation in apoptosis, and many results indicate that H1 dephosphorylation occurs during apoptosis. We and others hypothesized that cell cycle effects by the apoptosis inducers may have affected previous studies. In Paper II, the H1 phosphorylation pattern was investigated in early apoptosis in Jurkat cells, taking cell cycle effects into account. In receptor-mediated apoptosis, apoptosis occurs with a mainly preserved phosphorylation pattern, while Camptothecin induced apoptosis results in rapid dephosphorylation of H1 subtypes, demonstrating that H1 dephosphorylation is not a general event in apoptosis, but may occur upon apoptosis induction via the mitochondrial pathway. The dephosphorylation may also be a result of early cell cycle effects or signalling.Therefore, the H1 phosphorylation pattern in the cell cycle of normal activated T cells was investigated in Paper IV in this thesis. Some studies, which have been made using cancer cell lines from various species and cell synchronization, have indicated a sequential addition of phosphate groupsacross the cell cycle. Normal T cells and cell sorting by flow cytometry were used to circumvent side-effects from cell synchronization. The data demonstrate that a pattern with phosphorylated serines is established in late G1/early S phase, with some additional phosphorylation occurring during S, and further up-phosphorylation seems to occur during mitosis. Malignant transformation may lead to an altered G1 H1 phosphorylation pattern, as was demonstrated using sorted Jurkat T lymphoblastoid cells.

    During mitosis, certain H1 subtypes may be relocated to the cytoplasm. In Paper III, the location of histones H1.2, H1.3 and H1.5 during mitosis was investigated. Histone H1.3 was detected in cell nuclei in all mitotic stages, while H1.2 was detected in the nucleus during prophase and telophase, and primarily in the cytoplasm during metaphase and early anaphase. H1.5 was located mostly to chromatin during prophase and telophase, and to both chromatin and cytoplasm during metaphase and anaphase. Phosphorylated H1 was located in chromatin in prophase, and in both chromatin and cytoplasm during metaphase, anaphase and telophase, indicating that the mechanism for a possible H1 subtype relocation to the cytoplasm is phosphorylation.

    In conclusion, data obtained during this thesis work suggest that H1 histones and their phosphorylation may participate in the regulation of events in the cell cycle, such as S-phase progression and mitosis, possibly through altered interactions with chromatin, and/or by partial or complete removal of subtypes or phosphorylated variants from chromatin.

    List of papers
    1. Characterization of sequence variations in human histone H1.2 and H1.4 subtypes
    Open this publication in new window or tab >>Characterization of sequence variations in human histone H1.2 and H1.4 subtypes
    Show others...
    2005 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 272, no 14, p. 3673 -3683Article in journal (Refereed) Published
    Abstract [en]

    In humans, eight types of histone H1 exist (H1.1–H1.5, H1°, H1t and H1oo), all consisting of a highly conserved globular domain and less conserved N- and C-terminal tails. Although the precise functions of these isoforms are not yet understood, and H1 subtypes have been found to be dispensable for mammalian development, it is now clear that specific functions may be assigned to certain individual H1 subtypes. Moreover, microsequence variations within the isoforms, such as polymorphisms or mutations, may have biological significance because of the high degree of sequence conservation of these proteins. This study used a hydrophilic interaction liquid chromatographic method to detect sequence variants within the subtypes. Two deviations from wild-type H1 sequences were found. In K562 erythroleukemic cells, alanine at position 17 in H1.2 was replaced by valine, and, in Raji B lymphoblastoid cells, lysine at position 173 in H1.4 was replaced by arginine. We confirmed these findings by DNA sequencing of the corresponding gene segments. In K562 cells, a homozygous GCC→GTC shift was found at codon 18, giving rise to H1.2 Ala17Val because the initial methionine is removed in H1 histones. Raji cells showed a heterozygous AAA→AGA codon change at position 174 in H1.4, corresponding to the Lys173Arg substitution. The allele frequency of these sequence variants in a normal Swedish population was found to be 6.8% for the H1.2 GCC→GTC shift, indicating that this is a relatively frequent polymorphism. The AAA→AGA codon change in H1.4 was detected only in Raji cells and was not present in a normal population or in six other cell lines derived from individuals suffering from Burkitt's lymphoma. The significance of these sequence variants is unclear, but increasing evidence indicates that minor sequence variations in linker histones may change their binding characteristics, influence chromatin remodeling, and specifically affect important cellular functions.

    Place, publisher, year, edition, pages
    Wiley InterScience, 2005
    Keywords
    HILIC, linker histones, sequence variants, SNP, tumor cell lines
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16381 (URN)10.1111/j.1742-4658.2005.04793.x (DOI)
    Available from: 2009-01-20 Created: 2009-01-20 Last updated: 2017-12-14Bibliographically approved
    2. Histone H1 Dephosphorylation Is Not a General Feature in Early Apoptosis
    Open this publication in new window or tab >>Histone H1 Dephosphorylation Is Not a General Feature in Early Apoptosis
    Show others...
    2008 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 47, p. 7539-7547Article in journal (Refereed) Published
    Abstract [en]

    Histone H1 is a family of nucleosomal proteins that exist in a number of subtypes. These subtypes can be modified after translation in various ways, above all by phosphorylation. Increasing levels of H1 phosphorylation has been correlated with cell cycle progression, while both phosphorylation and dephosphorylation of histone H1 have been linked to the apoptotic process. Such conflicting results may depend on which various apoptosis-inducing agents cause apoptosis via different apoptotic pathways and often interfere with cell proliferation. Therefore, we investigated the relation between apoptosis and H1 phosphorylation in Jurkat cells after apoptosis induction via both the extrinsic and intrinsic pathways and by taking cell cycle effects into account. After apoptosis induction by anti-Fas, no significant dephosphorylation, as measured by capillary electrophoresis, or cell cycle-specific effects were detected. In contrast, H1 subtypes were rapidly dephosphorylated when apoptosis was induced by camptothecin. We conclude that histone H1 dephosphorylation is not connected to apoptosis in general but may be coupled to apoptosis by the intrinsic pathway or to concomitant growth inhibitory signaling.

    Place, publisher, year, edition, pages
    ACS Publications, 2008
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16382 (URN)10.1021/bi702311x (DOI)
    Available from: 2009-01-20 Created: 2009-01-20 Last updated: 2017-12-14Bibliographically approved
    3. Translocation of Histone H1 Subtypes Between Chromatin and Cytoplasm During Mitosis in Normal Human Fibroblasts
    Open this publication in new window or tab >>Translocation of Histone H1 Subtypes Between Chromatin and Cytoplasm During Mitosis in Normal Human Fibroblasts
    Show others...
    2010 (English)In: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 77A, no 5, p. 478-484Article in journal (Refereed) Published
    Abstract [en]

    Histone H1 is an important constituent of chromatin which undergoes major structural rearrangements during mitosis. However, the role of H1, multiple H1 subtypes and H1 phosphorylation is still unclear. In normal human fibroblasts, phosphorylated H1 was found located in nuclei during prophase and in both cytoplasm and condensed chromosomes during metaphase, anaphase and telophase as detected by immunocytochemistry. Moreover, we detected remarkable differences in the distribution of the histone H1 subtypes H1.2, H1.3 and H1.5 during mitosis. H1.2 was found in chromatin during prophase, and almost solely in the cytoplasm of metaphase and early anaphase cells. In late anaphase it appeared in both chromatin and cytoplasm, and again in chromatin during telophase. H1.5 distribution pattern resembled that of H1.2, but some H1.5 remained situated in chromatin during metaphase and early anaphase. H1.3 was detected in chromatin in all cell cycle phases. We propose therefore, that H1 subtype translocation during mitosis is controlled by phosphorylation, in combination with H1 subtype inherent affinity. We conclude that H1 subtypes, or their phosphorylated variants, may be signalling molecules in mitosis or that they leave chromatin in a regulated way to give access for chromatin condensing factors or transcriptional regulators during mitosis.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2010
    Keywords
    Histone H1, Chromatin, Cell cycle, Mitosis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16383 (URN)10.1002/cyto.a.20851 (DOI)000277174000009 ()20104577 (PubMedID)
    Available from: 2009-01-20 Created: 2009-01-20 Last updated: 2017-12-14Bibliographically approved
    4. Histone H1 interphase phosphorylation pattern becomes largely established during G1/S transition in proliferating cells
    Open this publication in new window or tab >>Histone H1 interphase phosphorylation pattern becomes largely established during G1/S transition in proliferating cells
    Show others...
    (English)Manuscript (Other academic)
    Abstract [en]

    Histone H1 is an important constituent of chromatin, and is believed to be involved in regulation of chromatin structure. During the cell cycle, chromatin becomes locally decondensed in S phase, highly condensed during metaphase and again decondensed before re-entry into G1. This has been connected to increasing phosphorylation of H1 histones during the cell cycle. However, many of these experiments have been performed in non-human and human cancer   cell lines, and by the use of cell synchronization techniques and cell cycle-arresting drugs. In this study, we have investigated the H1 subtype composition and phosphorylation pattern in the cell cycle. Exponentially growing normal human activated T cells and Jurkat lymphoblastoid cells were sorted by fluorescence activated cell sorting into G1, S and G2/M populations, without the use of cell cycle arresting drugs. We found that the H1.5 protein level increased after T-cell activation. Our data indicate that serine phosphorylation of H1 subtypes occurred to a large extent in late G1 phase or early S, while some additional serine phosphorylation took place during S, G2 and M phases. Furthermore, our data suggest that the newly synthesized H1 molecules during S phase also achieve a similar phosphorylation pattern as the previous ones. Jurkat cells showed more extended H1.5 phosphorylation in G1 compared with T cells, a difference that can be explained by faster cell growth and/or the presence of enhanced H1 kinase activity in G1 in Jurkat cells. In conclusion, our data is consistent with a model where a major part of interphase H1 serine phosphorylation takes place within a narrow time window during the G1/Stransition. This implies that H1 serine phosphorylation may be coupled to changes in chromatin structure necessary for DNA replication.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16384 (URN)
    Available from: 2009-01-20 Created: 2009-01-20 Last updated: 2010-01-14Bibliographically approved
  • 2.
    Gréen, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sarg, Bettina
    Division of Clinical Biochemistry, Biocenter, Innsbruck Medical University, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria.
    Gréen, Henrik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Lönn, Anita
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cellbiology.
    Lindner, Herbert
    Division of Clinical Biochemistry, Biocenter, Innsbruck Medical University, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria.
    Rundquist, Ingemar
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Histone H1 interphase phosphorylation pattern becomes largely established during G1/S transition in proliferating cellsManuscript (Other academic)
    Abstract [en]

    Histone H1 is an important constituent of chromatin, and is believed to be involved in regulation of chromatin structure. During the cell cycle, chromatin becomes locally decondensed in S phase, highly condensed during metaphase and again decondensed before re-entry into G1. This has been connected to increasing phosphorylation of H1 histones during the cell cycle. However, many of these experiments have been performed in non-human and human cancer   cell lines, and by the use of cell synchronization techniques and cell cycle-arresting drugs. In this study, we have investigated the H1 subtype composition and phosphorylation pattern in the cell cycle. Exponentially growing normal human activated T cells and Jurkat lymphoblastoid cells were sorted by fluorescence activated cell sorting into G1, S and G2/M populations, without the use of cell cycle arresting drugs. We found that the H1.5 protein level increased after T-cell activation. Our data indicate that serine phosphorylation of H1 subtypes occurred to a large extent in late G1 phase or early S, while some additional serine phosphorylation took place during S, G2 and M phases. Furthermore, our data suggest that the newly synthesized H1 molecules during S phase also achieve a similar phosphorylation pattern as the previous ones. Jurkat cells showed more extended H1.5 phosphorylation in G1 compared with T cells, a difference that can be explained by faster cell growth and/or the presence of enhanced H1 kinase activity in G1 in Jurkat cells. In conclusion, our data is consistent with a model where a major part of interphase H1 serine phosphorylation takes place within a narrow time window during the G1/Stransition. This implies that H1 serine phosphorylation may be coupled to changes in chromatin structure necessary for DNA replication.

  • 3.
    Gréen, Anna
    et al.
    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, Department of Clinical Pathology and Clinical Genetics.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden; Royal Institute Technology, Sweden; Science for Life Laboratory,{ School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Stockholm, Sweden.
    Rehnberg, Malin
    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, Department of Clinical Pathology and Clinical Genetics.
    Svensson, Anneli
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Gunnarsson, Cecilia
    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, Department of Clinical Pathology and Clinical Genetics.
    Jonasson, Jon
    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, Department of Clinical Pathology and Clinical Genetics.
    Assessment of HaloPlex Amplification for Sequence Capture and Massively Parallel Sequencing of Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes2015In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, no 1, p. 31-42Article in journal (Refereed)
    Abstract [en]

    The genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is complex. Mutations in genes encoding components of the cardiac desmosomes have been implicated as being causally related to ARVC. Next-generation sequencing allows parallel sequencing and duplication/deletion analysis of many genes simultaneously, which is appropriate for screening of mutations in disorders with heterogeneous genetic backgrounds. We designed and validated a next-generation sequencing test panel for ARVC using HaloPlex. We used SureDesign to prepare a HaloPlex enrichment system for sequencing of DES, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TGFB3, TMEM43, and TIN from patients with ARVC using a MiSeq instrument. Performance characteristics were determined by comparison with Sanger, as the gold standard, and TruSeq Custom Amplicon sequencing of DSC2, DSG2, DSP, JUP, and PKP2. All the samples were successfully sequenced after HaloPlex capture, with greater than99% of targeted nucleotides covered by greater than20x. The sequences were of high quality, although one problematic area due to a presumptive context-specific sequencing error causing motif Located in exon 1 of the DSP gene was detected. The mutations found by Sanger sequencing were also found using the HaloPlex technique. Depending on the bioinformatics pipeline, sensitivity varied from 99.3% to 100%, and specificity varied from 99.90/0 to 100%. Three variant positions found by Sanger and HaloPlex sequencing were missed by TruSeq Custom Amplicon owing to Loss of coverage.

  • 4.
    Gréen,, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lönn, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Holmgren Peterson, Kajsa
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Rundquist, Ingemar
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Translocation of Histone H1 Subtypes Between Chromatin and Cytoplasm During Mitosis in Normal Human Fibroblasts2010In: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 77A, no 5, p. 478-484Article in journal (Refereed)
    Abstract [en]

    Histone H1 is an important constituent of chromatin which undergoes major structural rearrangements during mitosis. However, the role of H1, multiple H1 subtypes and H1 phosphorylation is still unclear. In normal human fibroblasts, phosphorylated H1 was found located in nuclei during prophase and in both cytoplasm and condensed chromosomes during metaphase, anaphase and telophase as detected by immunocytochemistry. Moreover, we detected remarkable differences in the distribution of the histone H1 subtypes H1.2, H1.3 and H1.5 during mitosis. H1.2 was found in chromatin during prophase, and almost solely in the cytoplasm of metaphase and early anaphase cells. In late anaphase it appeared in both chromatin and cytoplasm, and again in chromatin during telophase. H1.5 distribution pattern resembled that of H1.2, but some H1.5 remained situated in chromatin during metaphase and early anaphase. H1.3 was detected in chromatin in all cell cycle phases. We propose therefore, that H1 subtype translocation during mitosis is controlled by phosphorylation, in combination with H1 subtype inherent affinity. We conclude that H1 subtypes, or their phosphorylated variants, may be signalling molecules in mitosis or that they leave chromatin in a regulated way to give access for chromatin condensing factors or transcriptional regulators during mitosis.

  • 5.
    Gréen, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sarg, Bettina
    DiVision of Clinical Biochemistry, Biocenter, Innsbruck Medical UniVersity, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria.
    Koutzamani, Elisavet
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Genheden, Ulrika
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Lindner, Herbert H.
    DiVision of Clinical Biochemistry, Biocenter, Innsbruck Medical UniVersity, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria.
    Rundquist, Ingemar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Histone H1 Dephosphorylation Is Not a General Feature in Early Apoptosis2008In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 47, p. 7539-7547Article in journal (Refereed)
    Abstract [en]

    Histone H1 is a family of nucleosomal proteins that exist in a number of subtypes. These subtypes can be modified after translation in various ways, above all by phosphorylation. Increasing levels of H1 phosphorylation has been correlated with cell cycle progression, while both phosphorylation and dephosphorylation of histone H1 have been linked to the apoptotic process. Such conflicting results may depend on which various apoptosis-inducing agents cause apoptosis via different apoptotic pathways and often interfere with cell proliferation. Therefore, we investigated the relation between apoptosis and H1 phosphorylation in Jurkat cells after apoptosis induction via both the extrinsic and intrinsic pathways and by taking cell cycle effects into account. After apoptosis induction by anti-Fas, no significant dephosphorylation, as measured by capillary electrophoresis, or cell cycle-specific effects were detected. In contrast, H1 subtypes were rapidly dephosphorylated when apoptosis was induced by camptothecin. We conclude that histone H1 dephosphorylation is not connected to apoptosis in general but may be coupled to apoptosis by the intrinsic pathway or to concomitant growth inhibitory signaling.

  • 6.
    Gréen, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Sarg, Bettina
    Innsbruck Medical University.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Lönn, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lindner, Herbert H
    Innsbruck Medical University.
    Rundquist, Ingemar
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Histone H1 interphase phosphorylation becomes largely established in G(1) or early S phase and differs in G(1) between T-lymphoblastoid cells and normal T cells2011In: EPIGENETICS and CHROMATIN, ISSN 1756-8935, Vol. 4, no 15Article in journal (Refereed)
    Abstract [en]

    Background: Histone H1 is an important constituent of chromatin, and is involved in regulation of its structure. During the cell cycle, chromatin becomes locally decondensed in S phase, highly condensed during metaphase, and again decondensed before re-entry into G(1). This has been connected to increasing phosphorylation of H1 histones through the cell cycle. However, many of these experiments have been performed using cell-synchronization techniques and cell cycle-arresting drugs. In this study, we investigated the H1 subtype composition and phosphorylation pattern in the cell cycle of normal human activated T cells and Jurkat T-lymphoblastoid cells by capillary electrophoresis after sorting of exponentially growing cells into G(1), S and G(2)/M populations. less thanbrgreater than less thanbrgreater thanResults: We found that the relative amount of H1.5 protein increased significantly after T-cell activation. Serine phosphorylation of H1 subtypes occurred to a large extent in late G(1) or early S phase in both activated T cells and Jurkat cells. Furthermore, our data confirm that the H1 molecules newly synthesized during S phase achieve a similar phosphorylation pattern to the previous ones. Jurkat cells had more extended H1.5 phosphorylation in G(1) compared with T cells, a difference that can be explained by faster cell growth and/or the presence of enhanced H1 kinase activity in G(1) in Jurkat cells. less thanbrgreater than less thanbrgreater thanConclusion: Our data are consistent with a model in which a major part of interphase H1 phosphorylation takes place in G(1) or early S phase. This implies that H1 serine phosphorylation may be coupled to changes in chromatin structure necessary for DNA replication. In addition, the increased H1 phosphorylation of malignant cells in G(1) may be affecting the G(1)/S transition control and enabling facilitated S-phase entry as a result of relaxed chromatin condensation. Furthermore, increased H1.5 expression may be coupled to the proliferative capacity of growth-stimulated T cells.

  • 7.
    Sandestig, Anna
    et al.
    Region Östergötland, Center for Diagnostics, Clinical genetics.
    Gréen, Anna
    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.
    Jonasson, Jon
    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.
    Vogt, Hartmut
    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, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Wahlström, Johan
    Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Pepler, Alexander
    Department of CeGaT GmbH, Tübingen, Germany.
    Ellnebo, Katarina
    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.
    Biskup, Saskia
    Department of CeGaT GmbH, Tübingen, Germany.
    Stefanova, Margarita
    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.
    Could Dissimilar Phenotypic Effects of ACTB Missense Mutations Reflect the Actin Conformational Change?: Two Novel Mutations and Literature Review2019In: Molecular Syndromology, ISSN 1661-8769, E-ISSN 1661-8777, Vol. 9, no 5, p. 259-265Article in journal (Refereed)
    Abstract [en]

    The beta-actin gene encodes 1 of 6 different actin proteins. De novo heterozygous missense mutations in ACTB have been identified in patients with Baraitser-Winter syndrome (BRWS) and also in patients with developmental disorders other than BRWS, such as deafness, dystonia, and neutrophil dysfunction. We describe 2 different novel de novo missense ACTB mutations, c.208Camp;gt;G (p.Pro70Ala) and c.511Camp;gt;T (p.Leu171Phe), found by trio exome sequencing analysis of 2 unrelated patients: an 8-year-old boy with a suspected BRWS and a 4-year-old girl with unclear developmental disorder. The mutated residue in the first case is situated in the actin H-loop, which is involved in actin polymerization. The mutated residue in the second case (p.Leu171Phe) is found at the actin barbed end in the W-loop, important for binding to profilin and other actin-binding molecules. While the boy presented with a typical BRWS facial appearance, the girl showed facial features not recognizable as a BRWS gestalt as well as ventricular arrhythmia, cleft palate, thrombocytopenia, and gray matter heterotopia. We reviewed previously published ACTB missense mutations and ascertained that a number of them do not cause typical BRWS. By comparing clinical and molecular data, we speculate that the phenotypic differences found in ACTB missense mutation carriers might supposedly be dependent on the conformational change of ACTB.

  • 8.
    Sarg, Bettina
    et al.
    Division of Clinical Biochemistry, Biocenter, Innsbruck Medical University, Austria.
    Gréen, Anna
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Helliger, Wilfried
    Division of Clinical Biochemistry, Biocenter, Innsbruck Medical University, Austria.
    Rundquist, Ingemar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Lindner, Herbert H.
    Division of Clinical Biochemistry, Biocenter, Innsbruck Medical University, Austria.
    Characterization of sequence variations in human histone H1.2 and H1.4 subtypes2005In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 272, no 14, p. 3673 -3683Article in journal (Refereed)
    Abstract [en]

    In humans, eight types of histone H1 exist (H1.1–H1.5, H1°, H1t and H1oo), all consisting of a highly conserved globular domain and less conserved N- and C-terminal tails. Although the precise functions of these isoforms are not yet understood, and H1 subtypes have been found to be dispensable for mammalian development, it is now clear that specific functions may be assigned to certain individual H1 subtypes. Moreover, microsequence variations within the isoforms, such as polymorphisms or mutations, may have biological significance because of the high degree of sequence conservation of these proteins. This study used a hydrophilic interaction liquid chromatographic method to detect sequence variants within the subtypes. Two deviations from wild-type H1 sequences were found. In K562 erythroleukemic cells, alanine at position 17 in H1.2 was replaced by valine, and, in Raji B lymphoblastoid cells, lysine at position 173 in H1.4 was replaced by arginine. We confirmed these findings by DNA sequencing of the corresponding gene segments. In K562 cells, a homozygous GCC→GTC shift was found at codon 18, giving rise to H1.2 Ala17Val because the initial methionine is removed in H1 histones. Raji cells showed a heterozygous AAA→AGA codon change at position 174 in H1.4, corresponding to the Lys173Arg substitution. The allele frequency of these sequence variants in a normal Swedish population was found to be 6.8% for the H1.2 GCC→GTC shift, indicating that this is a relatively frequent polymorphism. The AAA→AGA codon change in H1.4 was detected only in Raji cells and was not present in a normal population or in six other cell lines derived from individuals suffering from Burkitt's lymphoma. The significance of these sequence variants is unclear, but increasing evidence indicates that minor sequence variations in linker histones may change their binding characteristics, influence chromatin remodeling, and specifically affect important cellular functions.

  • 9.
    Smol, T.
    et al.
    CHU Lille, France; Univ Lille, France.
    Petit, F.
    Univ Lille, France; CHU Lille, France.
    Piton, A.
    Hop Univ Strasbourg, France.
    Keren, B.
    Grp Hosp Pitie Salpetriere, France.
    Sanlaville, D.
    Hosp Civils Lyon, France.
    Afenjar, A.
    Hop Enfants Armand Trousseau, France.
    Baker, S.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Bedoukian, E. C.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Bhoj, E. J.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Bonneau, D.
    CHU Angers, France.
    Boudry-Labis, E.
    CHU Lille, France.
    Bouquillon, S.
    CHU Lille, France.
    Boute-Benejean, O.
    Univ Lille, France; CHU Lille, France.
    Caumes, R.
    CHU Lille, France.
    Chatron, N.
    Hosp Civils Lyon, France.
    Colson, C.
    Univ Lille, France; CHU Lille, France.
    Coubes, C.
    CHU Montpellier, France.
    Coutton, C.
    CHU Grenoble Alpes, France.
    Devillard, F.
    CHU Grenoble Alpes, France.
    Dieux-Coeslier, A.
    Univ Lille, France; CHU Lille, France.
    Doco-Fenzy, M.
    CHU Reims, France.
    Ewans, L. J.
    Univ New South Wales, Australia.
    Faivre, L.
    CHU Dijon, France; CHU Dijon, France; Univ Bourgogne, France.
    Fassi, E.
    Washington Univ, MO 63110 USA.
    Field, M.
    Genet Learning Disabil Serv, Australia.
    Fournier, C.
    Hop Univ Strasbourg, France.
    Francannet, C.
    CHU Clermont Fernand, France.
    Genevieve, D.
    CHU Montpellier, France.
    Giurgea, I.
    Hop Trousseau, France.
    Goldenberg, A.
    CHU Rouen, France; CHU Rouen, France; Univ Rouen, France.
    Gréen, Anna
    Region Östergötland, Center for Diagnostics, Clinical genetics. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Guerrot, A. M.
    CHU Rouen, France; Univ Rouen, France.
    Heron, D.
    Grp Hosp Pitie Salpetriere, France.
    Isidor, B.
    CHU Nantes, France.
    Keena, B. A.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Krock, B. L.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Kuentz, P.
    Univ Bourgogne, France.
    Lapi, E.
    Anna Meyer Childrens Univ Hosp, Italy.
    Le Meur, N.
    CHU Rouen, France; Univ Rouen, France.
    Lesca, G.
    Hosp Civils Lyon, France.
    Li, D.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Marey, I.
    Grp Hosp Pitie Salpetriere, France.
    Mignot, C.
    Grp Hosp Pitie Salpetriere, France.
    Nava, C.
    Grp Hosp Pitie Salpetriere, France.
    Nesbitt, A.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Nicolas, G.
    CHU Rouen, France; Univ Rouen, France.
    Roche-Lestienne, C.
    CHU Lille, France.
    Roscioli, T.
    Univ New South Wales, Australia.
    Satre, V.
    CHU Grenoble Alpes, Grenoble, France.
    Santani, A.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Stefanova, Margarita
    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.
    Steinwall Larsen, S.
    Region Östergötland, Center for Diagnostics, Clinical genetics.
    Saugier-Veber, P.
    CHU Rouen, France; Univ Rouen, France.
    Picker-Minh, S.
    Charite Univ Med Berlin, Germany.
    Thuillier, C.
    CHU Lille, France.
    Verloes, A.
    Hop Robert Debre, France.
    Vieville, G.
    CHU Grenoble Alpes, France.
    Wenzel, M.
    Clinical Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.
    Willems, M.
    CHU Montpellier, France.
    Whalen, S.
    Grp Hosp Pitie Salpetriere, France.
    Zarate, Y. A.
    Univ Arkansas Med Sci, AR 72205 USA.
    Ziegler, A.
    CHU Angers, France.
    Manouvrier-Hanu, S.
    Univ Lille, France; CHU Lille, France.
    Kalscheuer, V. M.
    Max Planck Inst Mol Genet, Germany.
    Gerard, B.
    Hop Univ Strasbourg, France.
    Ghoumid, Jamal
    Univ Lille, France; CHU Lille, France.
    MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype2018In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 19, no 2, p. 93-103Article in journal (Refereed)
    Abstract [en]

    Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

  • 10.
    Trinks, Cecilia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Severinsson, Emelie A.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Holmlund, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Gréen, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Anna-Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Walz, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells2011In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 410, no 3, p. 422-427Article in journal (Refereed)
    Abstract [en]

    Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with canertinib at a concentration of 2 mu M caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.

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