LATE BREAKING NEWS E-POSTER PRESENTATION: LBP 4 Novel Epigenetic Small Molecule Approaches and Single-Cell Epigenetic Analysis for DMD

Abstract

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. Although DMD is a progressive degenerative disease, there is evidence for early, embryonic-stage defects in myogenesis and gene expression in DMD. By understanding how these defects initiate and contribute to DMD pathology, we may be better positioned to identify and utilize DMD therapies. Using single-cell RNAseq, we have identified one of the earliest known DMD phenotypes: a novel transcriptional trajectory of DMD human induced pluripotent stem cells (hiPSCs) undergoing myogenesis. Many of the dysregulated genes are involved in somitogenesis, advocating for a modified muscle development program in DMD cells. We are taking advantage of the zebrafish DMD model to identify conserved transcriptional dysregulation during embryonic development. We hypothesize that epigenetic drugs, small molecules that target chromatin modifications, can be used to ameliorate these early DMD transcriptional defects as well as improve DMD pathology. We performed a novel screen of an epigenetic small molecule library using DMD zebrafish and identified a novel combination of epigenetic drugs that rescues muscle degeneration in DMD zebrafish. To test the mechanisms of these new drugs, and to better characterize the epigenetic perturbations in DMD, we are testing whether epigenetic drugs correct the early transcriptional dysregulation observed in DMD hiPSCs and zebrafish embryos. Our studies support the combined use of zebrafish and hiPSCs as models for understanding the developmental epigenetic defects in DMD and for identifying new potential DMD therapies.