Structural Maintenance of Chromosomes flexible Hinge Domain-containing 1 (SMCHD1) is a non-canonical SMC protein that plays critical roles in epigenetic regulation including X chromosome inactivation, genomic imprinting and regulation of autosomal gene expression. Recently, mutations in SMCHD1 have been implicated in facioscapulohumeral muscular dystrophy (FSHD) and a rare craniofacial disorder called Bosma arhinia microphthalmia syndrome (BAM). While the importance of SMCHD1 is well-described, how SMCHD1 protein functions at the molecular level to mediate epigenetic control is still unclear.

We have undertaken a suite of genomics, structural-functional approaches to address this question. We demonstrated that SMCHD1 predominantly binds to regulatory sites in the genome, in part via its C-terminal SMC hinge domain. By performing small-angle X-ray studies, we obtained important insights into the structure and domain organisation of SMCHD1 protein. Furthermore, we established that the N-terminal region of SMCHD1 contains a catalytically active GHKL-type ATPase domain, potentially fuel an energy dependent conformational change of SMCHD1 necessary for its engagement with chromatin. Additionally, ongoing characterisation of recombinant proteins incorporating patient-derived SMCHD1 mutations have provided potential explanations to the underlying pathogenesis. Finally, our study has formed the basis of exploring activation of SMCHD1 as a potential therapeutic treatment for FSHD.