# Probing the myopathic activity of DUX4 using isogenic telomere-edited iPS cells

> **NIH NIH F31** · UNIVERSITY OF MINNESOTA · 2020 · $31,059

## Abstract

Project Summary
 Facioscapulohumeral Muscular Dystrophy (FSHD) is a dominant degenerative muscle disease with no
cure or treatment. The genetic cause of FSHD reduction of copy number of subtelomeric D4Z4 repeats at 4q35
encoding DUX4 homeobox protein, which is a potent transcription factor that is toxic to the cell. Contractions
lead to loss of repeat-induced silencing, allowing for transcription of DUX4. Interestingly, the complete absence
of D4Z4 repeats mimics the WT allele in that there is no pathologic consequence. Since D4Z4 is the last
element on chr4 before the telomere, deleting the end of chr4 effectively corrects the mutant allele. In this
study, I propose to use a genome engineering approach mediated by site-specific nucleases to delete the 4q35
telomeric region containing D4Z4 repeats, thus specifically eliminating DUX4. Targeted integration of an
artificial telomere to generate terminal chromosomal deletions has never been demonstrated before, and has a
unique application in FSHD, a dominant disease whose gene is the terminal gene on chromosome 4.
 A common diagnostic method for FSHD shows demethylation of D4Z4 using gDNA of blood cells, and
our lab has shown that D4Z4 is demethylated in FSHD iPS cells, meaning that any cell type in an FSHD
patient could be subject to deregulation by DUX4. We have previously shown that DUX4 recruits p300 to
induce global changes in histone acetylation, massively disrupting gene expression, thus pathology is not
obviously muscle-specific. Why the disease is muscle-specific and which cells in muscle may be deregulated
by DUX4 are unknowns. Because there is no evidence that DUX4 expression is myoblast or myofiber-specific,
I hypothesize that DUX4 might be misexpressed in non-myogenenic cells that are involved in myogenic
support, which would lead to FSHD pathogenic progression. These cell types have been largely overlooked in
the field. I will therefore generate a panel of isogenic pairs of corrected/diseased iPS lines, and study the
presence and consequence of DUX4 expression in myogenic as well as supportive cell types (obtained by
differentiating the iPS cells). Aim 1 will focus on the myogenic lineage and make use of xenograft models
pioneered by our collaborators, the Perlingeiro Lab. Aim 2 will focus on the supportive cell types and evaluate
cell non-autonomous effects on myogenesis. These studies will develop a unique and innovative method of
genome engineering and shed light on the pathophysiological mechanism of muscle degeneration in FSHD.

## Key facts

- **NIH application ID:** 10000825
- **Project number:** 5F31AR073642-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Natalya Aleksandra Goloviznina
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,059
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000825

## Citation

> US National Institutes of Health, RePORTER application 10000825, Probing the myopathic activity of DUX4 using isogenic telomere-edited iPS cells (5F31AR073642-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000825. Licensed CC0.

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