WEHI PhD Completion Seminar hosted by Professor Marnie Blewitt

Ruifeng Hu

PhD Student – Blewitt Laboratory, Genetics and Gene Regulation division, WEHI

Unravel the role of nucleic acid binding of the epigenetic regulator SMCHD1

 

Davis Auditorium

Join via SLIDO enter code #WEHIphdcompletion

Including Q&A session

Followed by refreshments in Tapestry Area

Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1) is a key epigenetic regulator shown to be critical for silencing of the inactive X chromosome and autosomal genes. Mutations in SMCHD1 are associated with human developmental disorders including Facioscapulohumeral muscular dystrophy (FSHD). The identified patient derived mutations locate in different regions of SMCHD1 protein and some of them affect SMCHD1’s functions like ATPase activity and nucleic acid binding ability.

In my PhD project, I generated novel mouse strains to investigate the role of nucleic acid binding of SMCHD1 by using a FSHD patient derived mutation R1867G, which was shown impairs SMCHD1’s nucleic acid binding ability in vitro. I observed R1867G mutant shows reduced enrichment at the inactive X chromosome by immunofluorescence, and further demonstrated that SMCHD1’s binding at conserved target sites is not affected by R1867G using ChIP-seq. I also investigated SMCHD1’s protein dynamics in live cells using Fluorescence Recovery After Photobleaching and Fluorescence Correlation Spectroscopy. I revealed nucleic acid binding restricts SMCHD1’s diffusion and play roles on maintaining but not loading SMCHD1 to its target loci. Finally, I investigated the effects of impaired nucleic binding of SMCHD1 to its function of gene silencing and interplay with epigenetic repressive marks H3K27me3 and H2AK119ub, demonstrated R1867G represents as a loss of function mutation.

Overall, my PhD works elucidates the role of SMCHD1’s nucleic acid binding ability in regulating its target binding, protein dynamics, and epigenetic repression functions, provides new insights to comprehensively understand molecular mechanisms of SMCHD1.

All welcome!