WEHI PhD Completion Seminar hosted by Professor Marnie Blewitt

Dr Anna Le Fevre
PhD Student – Blewitt Laboratory, Molecular Sciences division, WEHI

SMCHD1 at the human PWS locus

Davis Auditorium

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Including Q&A session

The human 15q11.2-13 locus is an imprinted region of the genome associated with Prader Willi syndrome (PWS). In PWS, normally active genes on the paternal allele are disrupted. 

Smchd1, a non-canonical SMC protein, is a large chromosomal ATPase that has been shown to mediate chromatin interactions. Smchd1 contributes to the epigenetic silencing of several clustered gene families, the inactive X chromosome and the PWS locus in mice. Activation of epigenetically silenced genes on the maternal allele presents a potential novel therapeutic approach for PWS and SMCHD1 may be an ideal target. 

To better understand SMCHD1 function at this human imprint, I have studied the maternal silenced PWS locus in PWS patient derived iPSCs and NPCs. SMCHD1 binds this region broadly in human cells and appears to act in opposition to CTCF, encouraging a closed chromatin conformation. In SMCHD1 KO cells we find a decrease in epigenetic marks associated with gene silencing, an increase in some active marks, localized increases in DNA accessibility and a change in chromatin looping and interactions across the locus. These changes are seen in the absence of significant transcription in pluripotent cells. The loss of SMCHD1 may prime pluripotent cells for gene activation upon differentiation to NPCs where we find gene activation from the imprinted maternal PWS locus. 

These findings show that SMCHD1 is highly relevant at the human PWS locus, binds broadly and acts across the locus. Data support further work targeting SMCHD1 as gene activation therapy for PWS and guide further work exploring SMCHD1 mechanism at this locus. 

All welcome!