Duchenne Muscular Dystrophy (DMD) is a fatal, genetic disease caused by the absence of a functional Dystrophin protein (Dys) at the sarcolemma of skeletal and cardiac muscles. Dys deficiency leads to several rounds of degeneration-regeneration of skeletal muscle ultimately resulting in the progressive replacement of contractile units with fibrotic scars and adipose tissue. Dys has been shown to protect myofiber’s bio-mechanical properties by stabilizing the sarcolemma integrity. Our and other labs discovered that dystrophin deficiency can also impair gene expression, thereby leading to altered patterns of gene expression (i.e. increased expression of the pro-fibrotic genes implicated in DMD pathogenesis). Given the important role of tri-dimensional chromatin interactions in regulating gene expression and the role of Dys in regulating various pathways potentially involved in gene regulation, (e.g, nNOS-HDAC2 and mechano-transduction pathway) we hypothesized that lack of Dys could alter the epigenetic landscape of DMD muscles. We have used a multiparametric approach to monitor changes of the epigenetic landscape at the genome-wide level in DMD myonuclei of human and mouse models of disease, and investigated the effect of Dys recovery, by micro-(µ-)Dys expression.
This analysis aims at elucidating the relationship between epigenetic alterations and altered patterns of gene expression and will determine whether “pathogenic” alterations of the epigenome in DMD muscle can be reverted, fully or partly, by µ-Dys restoration.