Mechanistic Insight into the Epigenetic Regulator SMCHD1 and its Implication in Diseases — ASN Events

Mechanistic Insight into the Epigenetic Regulator SMCHD1 and its Implication in Diseases (#170)

Kelan Chen 1 , Alexandra Gurzau 1 , Jiang Hu 2 , Darcy Moore 1 , Ruijie Liu 1 , Sarah Kessans 1 , Kelsey Breslin 1 , Samuel Young 1 , Clare Parish 3 , Silvère van der Maarel 4 , Isabelle Lucet 1 , Peter Czabotar 1 , Renwick Dobson 5 , Grant Pearce 5 , Matthew Ritchie 1 , Graham Kay 2 , James Murphy 1 , Marnie Blewitt 1
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. QIMR Berghofer Medical Research Institute, Brisbane, Australia
  3. Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
  4. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  5. University of Canterbury, Christchurch, New Zealand

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.    

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