Does Dystrophin Restoration Reverse Epigenetic and Transcriptional Pathogenic Features in Duchenne Muscular Dystrophy?
Abstract
The purpose of this project is to investigate the effect of dystrophin loss on 3D genome organization and gene expression output of skeletal myofibers, and to determine whether recovery of expression of a short form of dystrophin (micro-dystrophin) currently used in clinical trial with Duchenne Muscular Dystrophy (DMD) boys can restore in full or partly the original 3D nuclear landscape and gene expression. The goal of this research is the identification of pathological alterations in chromatin interactions than impair the expression of genes implicated in the pathogenesis of DMD. We have generated datasets of RNAseq, ATACseq and promoter capture HiC (pcHiC) from cultures of DMD muscles (or wild type controls), before or after micro-dystrophin re-expression. During the analysis of these samples, we have discovered that some samples did not reach the standard quality control check and therefore we have prepared and added more experimental replicates. We have completed the RNAseq and ATACseq analysis, while pcHiC is still undergoing. The analysis so far is showing that the absence of dystrophin causes profound changes in chromatin accessibility at regulatory elements of genes implicated in many features of DMD pathogenesis and disease progression, leading to deregulation of their expression. We found that re-expression of a micro-dystrophin (micro Dys5) without the nitric oxide (NO) binding domain could not rescue a large majority of these alterations, while reexpression of a micro-dystrophin (micro Dys5) that retains the nitric oxide (NO) binding domain could partly recover some of these alterations and restored some gene expression pattern to the levels of wild type myotubes.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1221809
Entities
People
- Pier L. Puri