Many genetic syndromes are linked to mutations in genes encoding factors that guide chromatin organization. Among them, several distinct rare genetic diseases are linked to mutations in SMCHD1 that encodes the structural maintenance of chromosomes flexible hinge domain containing 1 chromatin-associated factor. In humans, its function as well as the impact of its mutations remains poorly defined. To fill this gap, we determined the episignature associated with heterozygous SMCHD1 variants in primary cells and cell lineages derived from induced pluripotent stem cells for Bosma arhinia and microphthalmia syndrome (BAMS) and type 2 facioscapulohumeral dystrophy (FSHD2). In human tissues, SMCHD1 regulates the distribution of methylated CpGs, H3K27 trimethylation and CTCF at repressed chromatin but also at euchromatin. Based on the exploration of tissues affected either in FSHD or in BAMS, i.e. skeletal muscle fibers and neural crest stem cells, respectively, our results emphasize multiple functions for SMCHD1, in chromatin compaction, chromatin insulation and gene regulation with variable targets or phenotypical outcomes. We concluded that in rare genetic diseases, SMCHD1 variants impact gene expression in two ways: (i) by changing the chromatin context at a number of euchromatin loci or (ii) by directly regulating some loci encoding master transcription factors required for cell fate determination and tissue differentiation.
KAUST Repository Item: Exported on 2023-06-22
Acknowledgements: Association Française contre les Myopathies; Fondation Maladies Rares; Agence Nationale pour la Recherche [ANR-21-CE45-0001-01]; Ministry of Education, France (to C.D., C.L. and M.D.); FSH Society (to C.D); Aix-Marseille University [AMX-19-IET-007 to A.B.]; Agency for Science, Technology and Research (to B.R.); Ministry of Education, Singapore [MOE-T2EP30122-0005 to S.X.]; National University of Singapore (to S.X.). Funding for open access charge: Aix-Marseille University. We are indebted and thank all patients for participating in this study. We are thankful to Drs Claire Francastel and Stéphane Zaffran for critical comments on the work and manuscript. We acknowledge the GBiM genomics and bioinformatics core facility for RNA-seq and the Marseille Stem Cells core facility for stem cells. The graphical abstract was made using BioRender (agreement number K125AM4BGM). B.R. is an investigator of the National Research Foundation (Singapore) and Branco Weiss Foundation (Switzerland) and an EMBO Young Investigator.