Wednesday, April 24, 2024
4/24/2024
PROJECT SUMMARY Facioscapulohumeral dystrophy (FSHD) affects ~1/10,000 people and is caused by decreased epigenetic repression of the DUX4 retrogene with subsequent mis-expression of DUX4 in skeletal muscle. As increasing the SMCHD1-mediated epigenetic repression at the D4Z4 locus silences DUX4 in FSHD1 and FSHD2 muscle cells, this application will take a direct molecular biology approach to identify the diversity of SMCHD1 complexes and the role of each component in establishing and maintaining repressive chromatin structure at the D4Z4 and preventing DUX4 expression in skeletal muscle. The broad and long-term goal is to determine the functional components of the SMCHD1 complexes at the D4Z4 locus as a basis for future therapies directed at increasing epigenetic repression. The major hypothesis is that SMCHD1 forms different interactions depending on post- translational modification, chromatin association, and developmental state of the cell, and that understanding the functional roles of the different complexes will provide simple reductionist models for testing candidate interventions. Aim 1 will determine the proteins complexed with SMCHD1 at the D4Z4 locus and their functional significance, chromatin association, and SUMO dependence. Aim 2 will determine the composition of SMCHD1 complexes at autosomal single copy loci in the genome compared to repetitive regions and to subdomains of the D4Z4. Aim 3 will identify the relative roles of SMCHD1 complex components in the establishment and maintenance of epigenetic modifications during stem cell reprogramming and differentiation. Together, these aims will add clarity to the components of SMCHD1 complexes and their functional roles in D4Z4 epigenetic repression, and provide new opportunities to design interventions to suppress DUX4 expression as a treatment for FSHD.
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