# Mechanisms of DUX4 mediated FSHD pathology

> **NIH NIH R01** · UNIVERSITY OF NEVADA RENO · 2020 · $617,468

## Abstract

SUMMARY
Facioscapulohumeral Muscular Dystrophy (FSHD) is one of the most prevalent myopathies affecting
males and females of all ages, and currently there is no cure or therapeutic intervention available. The
long-term goal of this project is to determine the epigenetic mechanisms leading to pathogenic gene
expression in FSHD, and identify regulatory components that are viable targets for therapeutic
development. FSHD is a complex genetic and epigenetic disease caused by chromatin relaxation of
the D4Z4 macrosatellite repeat array at chromosome 4q35, which leads to aberrant expression of the
DUX4 gene from the distal-most repeat unit. The DUX4 protein, in turn, activates a host of genes
normally expressed in early development, which cause pathology when mis-expressed in adult
skeletal muscle. This established model of FSHD pathogenesis has stimulated the search for DUX4-
based therapeutic targets, including approaches to block DUX4 expression. While normal
mechanisms of D4Z4 repression have been well-characterized, very little is known about the factors
and pathways responsible for facilitating aberrant activation of DUX4. Previously, we showed that the
degree and stability of epigenetic dysregulation at the FSHD-associated 4q35 locus is the key
determinant for DUX4 expression, clinical presentation, and severity of FSHD pathology. Thus,
targeting epigenetic dysregulation in FSHD is a potentially powerful therapeutic avenue. Such an
approach would be greatly aided by a better understanding of the factors facilitating DUX4
expression, each of which represents a potential target for therapeutic inhibition. In a candidate-based
screen, we identified several epigenetic regulators with druggable domains that function as novel
activators of DUX4. Here, we will characterize these epigenetic facilitators of DUX4 expression and
validate their potential as therapeutic targets in FSHD. We will determine the global effects of
reducing the expression of these factors on skeletal muscle health and development using primary
patient cells and novel animal models. Finally, we will test the translational potential of inhibiting these
DUX4 regulators in an FSHD human xenograft mouse model derived from FSHD patient myoblasts
with their endogenous D4Z4 arrays. DUX4 regulators will be inhibited by CRISPR inhibition and
assayed for specificity. Successful completion of this project will provide key insights into the
mechanisms of epigenetic dysregulation in FSHD and validate the translational potential of novel
therapeutic targets in vivo.

## Key facts

- **NIH application ID:** 9916640
- **Project number:** 2R01AR062587-07A1
- **Recipient organization:** UNIVERSITY OF NEVADA RENO
- **Principal Investigator:** Peter L Jones
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $617,468
- **Award type:** 2
- **Project period:** 2013-07-03 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916640

## Citation

> US National Institutes of Health, RePORTER application 9916640, Mechanisms of DUX4 mediated FSHD pathology (2R01AR062587-07A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9916640. Licensed CC0.

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