# SMCHD1 Pathways as Candidate Targets for FSHD

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $417,286

## Abstract

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.

## Key facts

- **NIH application ID:** 10873271
- **Project number:** 5R01AR066248-11
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Stephen J Tapscott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $417,286
- **Award type:** 5
- **Project period:** 2014-04-25 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873271

## Citation

> US National Institutes of Health, RePORTER application 10873271, SMCHD1 Pathways as Candidate Targets for FSHD (5R01AR066248-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10873271. Licensed CC0.

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