# Pathogenic Alterations of the 3D Epigenetic Landscape in Dystrophin-Deficient Skeletal Muscles and Reversal by Dystrophin Re-Expression

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2022 · $676,726

## Abstract

PROJECT SUMMARY
Lack of dystrophin (dys) and disruption of the dys-associated protein complex (DAPC) at the membrane of
skeletal myofibers are widely recognized as the main cause of sarcolemma instability, leading to skeletal
muscle loss in patients affected by Duchenne Muscular Dystrophy (DMD). In addition to its structural function,
dys has been implicated in the regulation of additional downstream cellular events, including control of the
genome integrity and gene expression. Indeed, dys-deficient muscles exhibit altered profiles of histone
modifications, gene expression and non-coding RNA, as well as features of genomic instability and nuclear
abnormalities. Chromosome conformation capture (3C)-based studies have revealed that the genome is folded
into high-order chromatin interactions. Understanding the relationship between dys deficiency, dysregulated
gene expression and altered genome topology is of special interest for the complete understanding of DMD
pathogenesis and for the evaluation of the effective benefits of therapeutic approaches aimed at replacing dys
expression in DMD boys. This proposal addresses this question by exploiting state-of-the-art genome-wide
approaches (i.e. promoter capture-HiC, ChIP-seq, ATAC-seq and RNAseq) to detect perturbations of the
epigenetic landscape and transcriptome in DMD muscles, using two complementary experimental models –
patient iPSC-based in dish model of human DMD vivo and the mdx mouse model in vivo, by the following
Aims: Aim 1. To identify alterations in high-order chromatin interactions that regulate gene expression
in DMD muscles We will identify alterations of chromatin interactions between functional and structural
genomic elements, leading to pathogenic gene expression in human (hiPSC-derived skeletal muscles) and
mouse (mdx mice) models of DMD. Aim 2. Effect of µ-dys restoration on reversal of alterations in high-
order chromatin interactions that regulate gene expression in DMD muscles We will evaluate whether
restoration of dys expression by µ-dys reverses (partly or completely) the epigenetic and transcriptional
alterations of DMD muscles identified in Aim 1. Aim 3. Bioinformatic identification and analysis of
epigenetic and transcriptional alterations in DMD muscles We will perform an integrated bioinformatic
analysis of pcHi-C, RNA-seq, ATAC-seq and ChIP-seq data to identify DMD-associated pathogenic chromatin
interactions (DMD PCI) in DMD MuSCs and myofibers, and their susceptibility to µ-dys expression. Aim 4.
Contraction-induced alterations in high-order chromatin interactions at pathogenic loci in DMD
muscles and reversibility by dys restoration We will determine the effect of muscle contraction on PCI and
gene expression at loci of pathogenic genes, within the context of dys deficiency and upon µ-dys recovery.
Understanding whether dys deficiency causes epigenetic perturbations responsible for pathogenic
transcriptional output of DMD muscles, and whether they could be reversed...

## Key facts

- **NIH application ID:** 10367865
- **Project number:** 2R01AR056712-11A1
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Pier Lorenzo Puri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $676,726
- **Award type:** 2
- **Project period:** 2009-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367865

## Citation

> US National Institutes of Health, RePORTER application 10367865, Pathogenic Alterations of the 3D Epigenetic Landscape in Dystrophin-Deficient Skeletal Muscles and Reversal by Dystrophin Re-Expression (2R01AR056712-11A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10367865. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*