SMCHD1 variants may induce variegated expression in Facio Scapulo Humeral Dystophy and Bosma Arhinia and microphtalmia syndrome

Abstract

An expanding number of genetic syndromes are linked to mutations in genes encoding factors that guide chromatin organization. Recently, distinct genetic syndromes have been linked to mutations in the SMCHD1 gene. However, the function of this non-canonical SMC protein remains partly defined in Human tissues. To address this question, we determined its epi-signature in type 2 Facio Scapulo Humeral Dystrophy (FSHD2) and Bosma Arhinia and Microphtalmia Syndrome (BAMS) linked to heterozygous mutations in this gene. By combining RNA-Seq, DNA methylation profiling and ChIP-Seq, we showed that SMCHD1 regulates repressed chromatin but also cis-regulatory elements and enhancers. Our results emphasize dual functions for SMCHD1, in chromatin compaction, chromatin insulation and gene regulation with variable outcomes and targets depending on tissues. We propose that altered DNA methylation and long-range chromatin organization at a number of loci required for development and tissue differentiation, trigger variegated gene expression in rare genetic diseases linked to heterozygous SMCHD1 mutations.

SMCHD1 activates the expression of genes required for the expansion of human myoblasts

“…Consistent with previous findings (41) we observed the co-binding of CTCF at many of these SMCHD1bound enhancers (Supplementary Figure S4E). This indicates a role for SMCHD1 in helping establish active enhancers at genes involved in cell cycle regulation.…”

Telomere Position Effect Over Long Distance acts as a genome-wide epigenetic regulator through a commoncis- element

“…TRF2 is relocated towards the most telomeric sequences as telomere shortens, as previously suggested by others 32 . Likewise, regulation by SMCHD1 is possible but appears context-dependent, echoing previous work deciphering its role in Human 45,57,58 . Strikingly, the most consistent trans partner of TPE-OLD ( i .…”

“…TRF2 is relocated towards the most telomeric sequences as telomere shortens, as previously suggested by others 32 . Likewise, regulation by SMCHD1 is possible but appears context-dependent, echoing previous work deciphering its role in Human 45,57,58 . Strikingly, the most consistent trans partner of TPE-OLD (i.e., acts on WE element and is depleted at TPE-OLD loci upon telomere shortening), RBPJ, is a transcriptional factor that was found to function by triggering recruitment of chromatin remodeling complexes, including histone modifiers 59 ; suggesting a dynamic interaction with potential enhancers 60 .…”