Oral Presentation 46th Lorne Genome Conference 2025

Mechanisms of SMCHD1-induced gene silencing at the human 15q11.2-13 locus. (115499)

Anna LeFevre 1 2 , Tamara Cameron 1 2 , Kelsey Breslin 1 2 , Caleb Chew 1 2 , James Lancaster 1 , Megan Iminitoff 1 2 , Quentin Gouil 1 2 3 , Hannah Vanyai 1 2 , Andrew Keniry 1 2 , David Amor 2 4 , Marnie Blewitt 1 2
  1. WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH, Parkville, VIC, Australia
  2. Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  3. Olivia Newton-John Centre, Heidelberg, VIC, Australia
  4. Murdoch Children's Research Institute, Royal Children's Hospital , Parkville, VIC, Australia

The imprinted human 15q11.2-13 locus is associated with several currently incurable, genetic neurodevelopmental disorders, including Prader Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS). In both conditions, genes on the paternal allele that are normally active are disrupted. Due to genomic imprinting, genes on the maternal allele are epigenetically silenced. Activation of these genes presents a novel therapeutic approach for PWS and SYS. 

SMCHD1 is an epigenetic regulator that contributes to silencing of several clustered gene families, imprinted regions and the inactive X chromosome1-4. Understanding of SMCHD1 function at the imprinted 15q11.2-13 locus in human cells is limited. Proof of concept studies in mouse and human derived cell lines have demonstrated modest activation of maternal genes at this locus following SMCHD1 suppression.  Greater understanding of mechanisms underlying 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, mechanisms of epigenetic silencing are studied in SMCHD1 KO PWS patient-derived induced pluripotent stem cells, as these cells allow us to exclusively study the role of SMCHD1 on the imprinted maternal allele. We identified a depletion of H3K9me3 in the absence of SMCHD1. Moreover, we have observed enrichment of CTCF and H3K27me3 in the SMCHD1 KO context, reminiscent of what is observed in the mouse at other SMCHD1 targets3,4. These data suggest similar mechanisms are at play in human and at the 15q11.2-13 locus as at other SMCHD1 targets. We are now testing whether SMCHD1 is required to recruit the zinc finger protein normally required to recruit the H3K9 methyltransferase to the locus, the relationship of these changes to transcriptional changes at the locus and how these data relate to SMCHD1’s role in regulating 3D chromatin architecture.

 

 

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