SMCHD1 is an epigenetic regulator active in the epigenetic silencing of several clustered gene families, imprinted regions and the inactive X chromosome. SMCHD1 acts at the imprinted human 15q11.2-13 locus, a region associated with several genetic developmental disorders, including Prader Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS). In both conditions, the paternal and normally active allele of the genes responsible for the disease are disrupted. Due to genomic imprinting, the healthy maternal allele remains silent. Current treatments for PWS and SYS do not address the underlying cause of disease and have limited efficacy. Reactivation of genes on the epigenetically silenced maternal allele presents a potential therapeutic approach.
Understanding of SMCHD1 function in human cells is limited. Proof of concept studies in mouse and human derived cell lines performed in our laboratory have demonstrated a modest reactivation of genes within the 15q11.2-13 locus following SMCHD1 suppression. Greater understanding of the mechanisms that underly SMCHD1-induced gene silencing at this locus may identify ways that SMCHD1 function could be removed and identify co-regulators that could be harnessed in future therapy to augment the effects of SMCHD1 removal on gene activation.
Here, SMCHD1 effects are studied in SMCHD1 KO PWS patient-derived induced pluripotent stem cells from patients with a paternal deletion and a patient with maternal uniparental disomy at 15q11.2-13. These cells present an ideal system for study of gene silencing at this locus, as they present cell lines that have either one or two silent alleles and no active allele at 15q11.2-13. Mechanisms by which SMCHD1 enables silencing and how loss of SMCHD1 alters epigenetic marks at the PWS cluster will be explored by investigation of specific binding sites, up and downstream effects, impact on 3D chromatin architecture and interaction with other factors.