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  1. Article ; Online: CDCA7-associated global aberrant DNA hypomethylation translates to localized, tissue-specific transcriptional responses.

    Vukic, Maja / Chouaref, Jihed / Della Chiara, Veronica / Dogan, Serkan / Ratner, Fallon / Hogenboom, Jenna Z M / Epp, Trevor A / Chawengsaksophak, Kallayanee / Vonk, Kelly K D / Breukel, Cor / Ariyurek, Yavuz / San Leon Granado, David / Kloet, Susan L / Daxinger, Lucia

    Science advances

    2024  Volume 10, Issue 6, Page(s) eadk3384

    Abstract: Disruption of cell division cycle associated 7 (CDCA7) has been linked to aberrant DNA hypomethylation, but the impact of DNA methylation loss on transcription has not been investigated. Here, we show that CDCA7 is critical for maintaining global DNA ... ...

    Abstract Disruption of cell division cycle associated 7 (CDCA7) has been linked to aberrant DNA hypomethylation, but the impact of DNA methylation loss on transcription has not been investigated. Here, we show that CDCA7 is critical for maintaining global DNA methylation levels across multiple tissues in vivo. A pathogenic
    MeSH term(s) DNA ; DNA Methylation ; Protein Isoforms/genetics ; Repressor Proteins/genetics ; Transcription Factors/genetics ; Animals ; Mice ; Cell Cycle Proteins/metabolism ; Nuclear Proteins/metabolism
    Chemical Substances DNA (9007-49-2) ; Protein Isoforms ; Repressor Proteins ; Transcription Factors ; cdca7 protein, mouse ; Cell Cycle Proteins ; Nuclear Proteins
    Language English
    Publishing date 2024-02-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.adk3384
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A functional assay to classify ZBTB24 missense variants of unknown significance.

    Wu, Haoyu / Vonk, Kelly K D / van der Maarel, Silvère M / Santen, Gijs W E / Daxinger, Lucia

    Human mutation

    2019  Volume 40, Issue 8, Page(s) 1077–1083

    Abstract: Increasing use of next-generation sequencing technologies in clinical diagnostics allows large-scale discovery of genetic variants, but also results in frequent identification of variants of unknown significance (VUSs). Their classification into disease- ... ...

    Abstract Increasing use of next-generation sequencing technologies in clinical diagnostics allows large-scale discovery of genetic variants, but also results in frequent identification of variants of unknown significance (VUSs). Their classification into disease-causing and neutral variants is often hampered by the absence of robust functional tests. Here, we demonstrate that a luciferase reporter assay, in combination with ChIP-qPCR, reliably separates pathogenic ZBTB24 missense variants in the context of immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome from natural variants in healthy individuals and patients of other diseases. Application of our assay to two published ZBTB24 missense VUSs indicates that they are likely not to cause ICF2 syndrome. Furthermore, we show that rare gnomAD ZBTB24 missense variants in key residues of the C2H2-ZF domain lead to a loss of function phenotype that resembles ICF2, suggesting that these individuals are carriers of ICF syndrome. In summary, we have developed a robust functional test to validate missense variants in ZBTB24.
    MeSH term(s) Animals ; Cells, Cultured ; Chromatin Immunoprecipitation Sequencing/methods ; Face/abnormalities ; Genetic Predisposition to Disease ; Humans ; Luciferases/genetics ; Luciferases/metabolism ; Mice ; Models, Biological ; Mouse Embryonic Stem Cells/cytology ; Mouse Embryonic Stem Cells/metabolism ; Mutation, Missense ; Phenotype ; Primary Immunodeficiency Diseases/genetics ; Protein Domains ; Repressor Proteins/chemistry ; Repressor Proteins/genetics
    Chemical Substances Repressor Proteins ; ZBTB24 protein, human ; Luciferases (EC 1.13.12.-)
    Language English
    Publishing date 2019-06-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1126646-6
    ISSN 1098-1004 ; 1059-7794
    ISSN (online) 1098-1004
    ISSN 1059-7794
    DOI 10.1002/humu.23786
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3586: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: The role of MORC3 in silencing transposable elements in mouse embryonic stem cells.

    Desai, Varsha P / Chouaref, Jihed / Wu, Haoyu / Pastor, William A / Kan, Ryan L / Oey, Harald M / Li, Zheng / Ho, Jamie / Vonk, Kelly K D / San Leon Granado, David / Christopher, Michael A / Clark, Amander T / Jacobsen, Steven E / Daxinger, Lucia

    Epigenetics & chromatin

    2021  Volume 14, Issue 1, Page(s) 49

    Abstract: Background: Microrchidia proteins (MORCs) are involved in epigenetic gene silencing in a variety of eukaryotic organisms. Deletion of MORCs result in several developmental abnormalities and their dysregulation has been implicated in developmental ... ...

    Abstract Background: Microrchidia proteins (MORCs) are involved in epigenetic gene silencing in a variety of eukaryotic organisms. Deletion of MORCs result in several developmental abnormalities and their dysregulation has been implicated in developmental disease and multiple cancers. Specifically, mammalian MORC3 mutations are associated with immune system defects and human cancers such as bladder, uterine, stomach, lung, and diffuse large B cell lymphomas. While previous studies have shown that MORC3 binds to H3K4me3 in vitro and overlaps with H3K4me3 ChIP-seq peaks in mouse embryonic stem cells, the mechanism by which MORC3 regulates gene expression is unknown.
    Results: In this study, we identified that mutation in Morc3 results in a suppressor of variegation phenotype in a Modifiers of murine metastable epialleles Dominant (MommeD) screen. We also find that MORC3 functions as an epigenetic silencer of transposable elements (TEs) in mouse embryonic stem cells (mESCs). Loss of Morc3 results in upregulation of TEs, specifically those belonging to the LTR class of retrotransposons also referred to as endogenous retroviruses (ERVs). Using ChIP-seq we found that MORC3, in addition to its known localization at H3K4me3 sites, also binds to ERVs, suggesting a direct role in regulating their expression. Previous studies have shown that these ERVs are marked by the repressive histone mark H3K9me3 which plays a key role in their silencing. However, we found that levels of H3K9me3 showed only minor losses in Morc3 mutant mES cells. Instead, we found that loss of Morc3 resulted in increased chromatin accessibility at ERVs as measured by ATAC-seq.
    Conclusions: Our results reveal MORC3 as a novel regulator of ERV silencing in mouse embryonic stem cells. The relatively minor changes of H3K9me3 in the Morc3 mutant suggests that MORC3 acts mainly downstream of, or in a parallel pathway with, the TRIM28/SETDB1 complex that deposits H3K9me3 at these loci. The increased chromatin accessibility of ERVs in the Morc3 mutant suggests that MORC3 may act at the level of chromatin compaction to effect TE silencing.
    MeSH term(s) Adenosine Triphosphatases/metabolism ; Animals ; Chromatin ; DNA Transposable Elements ; DNA-Binding Proteins/metabolism ; Endogenous Retroviruses/genetics ; Endogenous Retroviruses/metabolism ; Gene Silencing ; Mice ; Mouse Embryonic Stem Cells/metabolism
    Chemical Substances Chromatin ; DNA Transposable Elements ; DNA-Binding Proteins ; Adenosine Triphosphatases (EC 3.6.1.-) ; MORC3 protein, mouse (EC 3.6.1.-)
    Language English
    Publishing date 2021-10-27
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2462129-8
    ISSN 1756-8935 ; 1756-8935
    ISSN (online) 1756-8935
    ISSN 1756-8935
    DOI 10.1186/s13072-021-00420-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Hypomethylation of ERVs in the sperm of mice haploinsufficient for the histone methyltransferase Setdb1 correlates with a paternal effect on phenotype.

    Daxinger, Lucia / Oey, Harald / Isbel, Luke / Whitelaw, Nadia C / Youngson, Neil A / Spurling, Alex / Vonk, Kelly K D / Whitelaw, Emma

    Scientific reports

    2016  Volume 6, Page(s) 25004

    Abstract: The number of reports of paternal epigenetic influences on the phenotype of offspring in rodents is increasing but the molecular events involved remain unclear. Here, we show that haploinsufficiency for the histone 3 lysine 9 methyltransferase Setdb1 in ... ...

    Abstract The number of reports of paternal epigenetic influences on the phenotype of offspring in rodents is increasing but the molecular events involved remain unclear. Here, we show that haploinsufficiency for the histone 3 lysine 9 methyltransferase Setdb1 in the sire can influence the coat colour phenotype of wild type offspring. This effect occurs when the allele that directly drives coat colour is inherited from the dam, inferring that the effect involves an "in trans" step. The implication of this finding is that epigenetic state of the sperm can alter the expression of genes inherited on the maternally derived chromosomes. Whole genome bisulphite sequencing revealed that Setdb1 mutant mice show DNA hypomethylation at specific classes of transposable elements in the sperm. Our results identify Setdb1 as a paternal effect gene in the mouse and suggest that epigenetic inheritance may be more likely in individuals with altered levels of epigenetic modifiers.
    Language English
    Publishing date 2016--26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/srep25004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The prebiotic inulin modulates gut microbiota but does not ameliorate atherosclerosis in hypercholesterolemic APOE*3-Leiden.CETP mice.

    Hoving, Lisa R / Katiraei, Saeed / Pronk, Amanda / Heijink, Marieke / Vonk, Kelly K D / Amghar-El Bouazzaoui, Fatiha / Vermeulen, Rosalie / Drinkwaard, Lizette / Giera, Martin / van Harmelen, Vanessa / Willems van Dijk, Ko

    Scientific reports

    2018  Volume 8, Issue 1, Page(s) 16515

    Abstract: Gut microbiota have been implicated in the development of atherosclerosis and cardiovascular disease. Since the prebiotic inulin is thought to beneficially affect gut microbiota, we aimed to determine the effect of inulin supplementation on ... ...

    Abstract Gut microbiota have been implicated in the development of atherosclerosis and cardiovascular disease. Since the prebiotic inulin is thought to beneficially affect gut microbiota, we aimed to determine the effect of inulin supplementation on atherosclerosis development in APOE*3-Leiden.CETP (E3L.CETP) mice. Female E3L.CETP mice were fed a western-type diet containing 0.1% or 0.5% cholesterol with or without 10% inulin. The effects of inulin were determined on: microbiota composition, cecal short-chain fatty acid (SCFA) levels, plasma lipid levels, atherosclerosis development, hepatic morphology and hepatic inflammation. Inulin with 0.5% dietary cholesterol increased specific bacterial genera and elevated levels of cecal SCFAs, but did not affect plasma cholesterol levels or atherosclerosis development. Surprisingly, inulin resulted in mild hepatic inflammation as shown by increased expression of inflammation markers. However, these effects were not accompanied by increased hepatic macrophage number. Analogously, inulin induced mild steatosis and increased hepatocyte size, but did not affect hepatic triglyceride content. Inulin with 0.1% dietary cholesterol did not affect hepatic morphology, nor hepatic expression of inflammation markers. Overall, inulin did not reduce hypercholesterolemia or atherosclerosis development in E3L.CETP mice despite showing clear prebiotic activity, but resulted in manifestations of hepatic inflammation when combined with a high percentage of dietary cholesterol.
    MeSH term(s) Animals ; Apolipoprotein E3/genetics ; Apolipoprotein E3/metabolism ; Atherosclerosis/genetics ; Atherosclerosis/immunology ; Atherosclerosis/metabolism ; Bacteria/classification ; Bacteria/drug effects ; Bacteria/genetics ; Bacteria/isolation & purification ; DNA, Bacterial/genetics ; DNA, Ribosomal/genetics ; Diet, Western/adverse effects ; Disease Models, Animal ; Fatty Acids/chemistry ; Female ; Gastrointestinal Microbiome/drug effects ; Hypercholesterolemia/chemically induced ; Hypercholesterolemia/genetics ; Hypercholesterolemia/immunology ; Hypercholesterolemia/metabolism ; Inulin/administration & dosage ; Inulin/pharmacology ; Lipids/blood ; Mice ; Mice, Transgenic ; Phylogeny ; Prebiotics/administration & dosage ; RNA, Ribosomal, 16S/genetics ; Sequence Analysis, DNA
    Chemical Substances Apolipoprotein E3 ; DNA, Bacterial ; DNA, Ribosomal ; Fatty Acids ; Lipids ; Prebiotics ; RNA, Ribosomal, 16S ; apolipoprotein E3 (Leidein) ; Inulin (9005-80-5)
    Language English
    Publishing date 2018-11-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-018-34970-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Converging disease genes in ICF syndrome: ZBTB24 controls expression of CDCA7 in mammals.

    Wu, Haoyu / Thijssen, Peter E / de Klerk, Eleonora / Vonk, Kelly K D / Wang, Jun / den Hamer, Bianca / Aytekin, Caner / van der Maarel, Silvère M / Daxinger, Lucia

    Human molecular genetics

    2016  Volume 25, Issue 18, Page(s) 4041–4051

    Abstract: For genetically heterogeneous diseases a better understanding of how the underlying gene defects are functionally interconnected will be important for dissecting disease etiology. The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) ... ...

    Abstract For genetically heterogeneous diseases a better understanding of how the underlying gene defects are functionally interconnected will be important for dissecting disease etiology. The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome is a chromatin disorder characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS Here, we generated a Zbtb24 BTB domain deletion mouse and found that loss of functional Zbtb24 leads to early embryonic lethality. Transcriptome analysis identified Cdca7 as the top down-regulated gene in Zbtb24 homozygous mutant mESCs, which can be restored by ectopic ZBTB24 expression. We further demonstrate enrichment of ZBTB24 at the CDCA7 promoter suggesting that ZBTB24 can function as a transcription factor directly controlling Cdca7 expression. Finally, we show that this regulation is conserved between species and that CDCA7 levels are reduced in patients carrying ZBTB24 nonsense mutations. Together, our findings demonstrate convergence of the two ICF genes ZBTB24 and CDCA7 at the level of transcription.
    MeSH term(s) Animals ; Codon, Nonsense/genetics ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA Helicases/genetics ; Face/abnormalities ; Face/physiopathology ; Female ; Gene Expression Regulation, Developmental ; Humans ; Immunologic Deficiency Syndromes/genetics ; Immunologic Deficiency Syndromes/physiopathology ; Male ; Mice ; Mouse Embryonic Stem Cells/metabolism ; Nuclear Proteins/biosynthesis ; Nuclear Proteins/genetics ; Primary Immunodeficiency Diseases ; Repressor Proteins/genetics ; Transcription, Genetic ; Transcriptome/genetics ; DNA Methyltransferase 3B
    Chemical Substances CDCA7 protein, human ; Codon, Nonsense ; Nuclear Proteins ; Repressor Proteins ; ZBTB24 protein, human ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNA Helicases (EC 3.6.4.-) ; HELLS protein, human (EC 5.99.-)
    Language English
    Publishing date 2016-07-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddw243
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3469: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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