Send to

Choose Destination
Nucleic Acids Res. 2019 Apr 8;47(6):2822-2839. doi: 10.1093/nar/gkz005.

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

Author information

Aix Marseille Univ, INSERM MMG, Nerve and Muscle Department, Marseille, France.
NIHR Biomedical Research Centre, University College London, Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust, 30 Guilford Street, London WC1N 1EH, UK.
Institute of Molecular and Cell Biology, A*STAR, Singapore. Institute of Medical Biology, A*STAR, Singapore.
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; The Department of Medical Biology, University of Melbourne, Melbourne, Australia.
Institut de Génétique Humaine UMR9002 CNRS-Université de Montpellier. France.
Laboratory of Embryology and Genetics of Human Malformation, INSERM UMR 1163, Institut Imagine, Paris, France.
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
Département de Génétique Médicale et Biologie Cellulaire, AP-HM, Hôpital de la Timone enfants, Marseille, France.
Centre de ressources biologiques, AP-HM, Hôpital de la Timone enfants, Marseille, France.
Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
Centre de Génomique Humaine et Genopath, Faculté de Médecine et de Pharmacie, Université Mohammed V, 10100 Rabat, Morocco.
Institute of Human Genetics, University Medical Campus Göttingen, 37073 Göttingen, Germany.
Centre de références pour les maladies neuromusculaires et la SLA, AP-HM, Hôpital de la Timone, Marseille, France.
Department of Paediatrics, National University of Singapore, Singapore, Singapore.
Medical Genetics Department, Koç University School of Medicine (KUSOM), Istanbul, Turkey.
Reproductive Biology Laboratory, Academic Medical Center (AMC), Amsterdam-Zuidoost, The Netherlands.


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center