Mechanistic and structure-function characterisation of the epigenetic regulator SMCHD1

K Chen1,2, JM Murphy1,2 and ME Blewitt1,2

  1. The Walter and Eliza Hall Institute of Medical Research
  2. The University of Melbourne

Structural Maintenance of Chromosomes flexible Hinge Domain-containing 1 (SMCHD1) is an epigenetic regulator that plays critical roles in modulating gene expression. Recently, heterozygous loss of function mutations in SMCHD1 were identified in facioscapulohumeral muscular dystrophy (FSHD) patients, leading to ectopic expression of the disease-causing gene DUX4 in muscle cells. While the consequence of SMCHD1 deficiency is well-described, the fundamental question remains as to how SMCHD1 mediates epigenetic control at the molecular level. We have undertaken a suite of genomics, structural-functional approaches to address this question. We determined genome-wide SMCHD1 binding sites and found SMCHD1 binding at several of its known target genes is correlated with differential gene expression and concomitant changes in epigenetic marks. We also found that SMCHD1 predominantly binds to regulatory sites in the genome, in part via its C-terminal SMC hinge domain. In addition, by performing small-angle X-ray studies, we obtained important insights into the structure and domain organisation of SMCHD1 protein. Moreover, 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. We now focus on investigating how pathogenic mutations found in the ATPase domain of SMCHD1 alter its function and how to enhance SMCHD1's ATPase activity as a potential therapy to combat FSHD.