Use of snRNA-seq to characterize the skeletal muscle microenvironment during pathogenesis in FSHD


Translational Research

Poster Number: Virtual


Anugraha Raman, PhD, Fulcrum Therapeutics, Inc., Anthony Accorsi, PhD, Fulcrum Therapeutics, Inc., Michelle L Mellion, MD, Fulcrum Therapeutics, Inc., Bobby Riehle, PhD, Fulcrum Therapeutics, Inc., Lucienne Ronco, PhD, Fulcrum Therapeutics, Inc., L. Alejandro Rojas, PhD, Fulcrum Therapeutics, Inc., Christopher Moxham, PhD, Fulcrum Therapeutics, Inc.

Facioscapulohumeral muscular dystrophy (FSHD), one of the most common forms of muscular dystrophy, is a rare monogenic disease that currently has no effective treatment. It is caused by deletions of the macrosatellite D4Z4 repeats at sub-telomeric region of chromosome 4q35. Deletions to repeat numbers less than 10 within this region cause chromatin de-repression resulting in stochastic and aberrant expression of the embryonic transcription factor DUX4in skeletal muscle.The expression of DUX4 is myotoxic and results in muscle weakness in facial muscles and around the shoulder, eventually progressing to lower extremity and truncal weakness. While the root cause of FSHD has been elucidated, the molecular and cellular microenvironmental underpinnings that drive the loss of muscle tissue and function are not well understood. Here we describe the first characterization of human FSHD skeletal muscle biopsies using single nuclear RNA-sequencing (snRNAseq). Our goal is to understand the dynamic FSHD microenvironment at higher resolution. Analysis of these snRNA-seq profiles suggests an increase in relative populations of infiltrating immune cells and expansion of resident progenitor cell populations in FSHD versus healthy biopsies. In addition to expanded intercellular heterogeneity within the FSHD microenvironment, we also see a significant intracellular heterogeneity suggestive of altered cell states within diseased muscle. Characterization of these FSHD muscle biopsies will help us understand the processes contributing to FSHD pathogenesis, thereby enabling new target/therapeutic hypotheses.