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SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease.
Tapia Del Fierro, Andres; den Hamer, Bianca; Benetti, Natalia; Jansz, Natasha; Chen, Kelan; Beck, Tamara; Vanyai, Hannah; Gurzau, Alexandra D; Daxinger, Lucia; Xue, Shifeng; Ly, Thanh Thao Nguyen; Wanigasuriya, Iromi; Iminitoff, Megan; Breslin, Kelsey; Oey, Harald; Krom, Yvonne D; van der Hoorn, Dinja; Bouwman, Linde F; Johanson, Timothy M; Ritchie, Matthew E; Gouil, Quentin A; Reversade, Bruno; Prin, Fabrice; Mohun, Timothy; van der Maarel, Silvère M; McGlinn, Edwina; Murphy, James M; Keniry, Andrew; de Greef, Jessica C; Blewitt, Marnie E.
Afiliação
  • Tapia Del Fierro A; The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
  • den Hamer B; The Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
  • Benetti N; Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
  • Jansz N; The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
  • Chen K; The Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
  • Beck T; The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
  • Vanyai H; The Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
  • Gurzau AD; The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
  • Daxinger L; The Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
  • Xue S; The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
  • Ly TTN; Crick Advanced Light Microscopy Facility, The Francis Crick Institute, London, UK.
  • Wanigasuriya I; The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
  • Iminitoff M; The Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
  • Breslin K; Queensland Institute of Medical Research, Brisbane, QLD, Australia.
  • Oey H; Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
  • Krom YD; Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
  • van der Hoorn D; Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
  • Bouwman LF; Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
  • Johanson TM; The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
  • Ritchie ME; The Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
  • Gouil QA; The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
  • Reversade B; The Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
  • Prin F; The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
  • Mohun T; Queensland Institute of Medical Research, Brisbane, QLD, Australia.
  • van der Maarel SM; Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
  • McGlinn E; Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
  • Murphy JM; Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
  • Keniry A; The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
  • de Greef JC; The Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
  • Blewitt ME; The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Nat Commun ; 14(1): 5466, 2023 09 25.
Article em En | MEDLINE | ID: mdl-37749075
The interplay between 3D chromatin architecture and gene silencing is incompletely understood. Here, we report a novel point mutation in the non-canonical SMC protein SMCHD1 that enhances its silencing capacity at endogenous developmental targets. Moreover, it also results in enhanced silencing at the facioscapulohumeral muscular dystrophy associated macrosatellite-array, D4Z4, resulting in enhanced repression of DUX4 encoded by this repeat. Heightened SMCHD1 silencing perturbs developmental Hox gene activation, causing a homeotic transformation in mice. Paradoxically, the mutant SMCHD1 appears to enhance insulation against other epigenetic regulators, including PRC2 and CTCF, while depleting long range chromatin interactions akin to what is observed in the absence of SMCHD1. These data suggest that SMCHD1's role in long range chromatin interactions is not directly linked to gene silencing or insulating the chromatin, refining the model for how the different levels of SMCHD1-mediated chromatin regulation interact to bring about gene silencing in normal development and disease.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cromatina / Proteínas Cromossômicas não Histona / Distrofia Muscular Facioescapuloumeral Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cromatina / Proteínas Cromossômicas não Histona / Distrofia Muscular Facioescapuloumeral Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article