SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite

SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite

Nucleic Acids Research

10.1093/nar/gkz005

https://doi.org/10.1093/nar/gkz005

Camille Dion, Stéphane Roche, Camille Laberthonnière, Natacha Broucqsault, Virginie Mariot, Shifeng Xue, Alexandra D. Gurzau, Agnieszka Nowak, Christopher T. Gordon, Marie-Cécile Gaillard, Claire El-Yazidi, Morgane Thomas, Andrée Schlupp-Robaglia, Chantal Missirian, Valérie Malan, Liham Ratbi, Abdelaziz Sefiani, Bernd Wollnik, Bernard Binetruy, Emmanuelle Salort Campana, Shahram Attarian, Rafaelle Bernard, Karine Nguyen, Jeanne Amiel, Julie Dumonceaux, James M. Murphy, Jérôme Déjardin, Marnie E. Blewitt, Bruno Reversade, Jérôme D. Robin, Frédérique Magdinier

30 January 2019

Camille Dion, Stéphane Roche, Camille Laberthonnière, Natacha Broucqsault, Virginie Mariot, Shifeng Xue, Alexandra D Gurzau, Agnieszka Nowak, Christopher T Gordon, Marie-Cécile Gaillard, Claire El-Yazidi, Morgane Thomas, Andrée Schlupp-Robaglia, Chantal Missirian, Valérie Malan, Liham Ratbi, Abdelaziz Sefiani, Bernd Wollnik, Bernard Binetruy, Emmanuelle Salort Campana, Shahram Attarian, Rafaelle Bernard, Karine Nguyen, Jeanne Amiel, Julie Dumonceaux, James M Murphy, Jérôme Déjardin, Marnie E Blewitt, Bruno Reversade, Jérôme D Robin, Frédérique Magdinier, SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite, Nucleic Acids Research, Volume 47, Issue 6, 08 April 2019, Pages 2822–2839, https://doi.org/10.1093/nar/gkz005

The DNA methylation epigenetic signature is a key determinant during development. Rules governing its establishment and maintenance remain elusive especially at repetitive sequences, which account for the majority of methylated CGs. DNA methylation is altered in a number of diseases including those linked to mutations in factors that modify chromatin. Among them, SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain Containing 1) has been of major interest following identification of germline mutations in Facio-Scapulo-Humeral Dystrophy (FSHD) and in an unrelated developmental disorder, Bosma Arhinia Microphthalmia Syndrome (BAMS). By investigating why germline SMCHD1 mutations lead to these two different diseases, we uncovered a role for this factor in de novo methylation at the pluripotent stage. SMCHD1 is required for the dynamic methylation of the D4Z4 macrosatellite upon reprogramming but seems dispensable for methylation maintenance. We find that FSHD and BAMS patient's cells carrying SMCHD1 mutations are both permissive for DUX4 expression, a transcription factor whose regulation has been proposed as the main trigger for FSHD. These findings open new questions as to what is the true aetiology for FSHD, the epigenetic events associated with the disease thus calling the current model into question and opening new perspectives for understanding repetitive DNA sequences regulation.

http://creativecommons.org/licenses/by-nc/4.0/

Association Franc¸aise contre lesMyopathies (AFM) [MNHDecrypt and TRIM-RD]; Agence Nationale de la Recherche [ANR-13-BSV1-0001]; Fondation Aix-Marseille Universit´e, Sant´e, Sport et d´eveloppement Durable (to F.M.); C.D. was the recipient of a fellowship from the French Ministry of Education and FSH Society; C.L. is the recipient of a fellowship from the French Ministry of Education; A.G. was supported by a research training program scholarship from the Australian government; M.E.B. was supported by a Bellberry-Viertel senior medical research fellowship; J.M.M. was supported by Australian National Health and Medical Research Council (NHMRC) fellowship [1105754];M.E.B. and J.M.M. acknowledge NHMRC grant [1098290]; Independent Research Institute Infrastructure Scheme (IRIISS) [9000433] support, and Victorian State Government Operational Infrastructure Support. Funding for open access charge: Aix Marseille Univ.

https://oar.a-star.edu.sg/communities-collections/articles/15165

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Institute of Molecular and Cell Biology