Reciprocal regulation between the protein arginine deiminases and mSWI/SNF chromatin remodelers controls skeletal muscle differentiation and regeneration

Abstract

Protein arginine deiminases (PADs) post-translationally convert arginine to citrulline on target proteins and serve as regulators of multiple cellular functions. PAD enzymes have been implicated in autoimmune disorders, cancer, and other diseases. Inhibiting PAD activity is currently being pursued clinically for therapeutic purposes. However, little is known about PAD function in normal developmental or homeostatic processes. Here we show that multiple PAD isoforms contribute to primary myoblast differentiation by binding to regulatory regions of target genes. Furthermore, we demonstrate a novel, reciprocal requirement for PADs and mammalian SWI/SNF (mSWI/SNF) chromatin remodeling enzymes; PAD enzymes are required for the expression and binding of specific mSWI/SNF enzyme subunits to target gene regulatory sequences while mSWI/SNF enzymes are required for the expression and binding of PAD enzymes. In vivo, the PADs contribute to mouse skeletal muscle regeneration after injury, with PAD4 specifically identified as a required regulator. This work identifies the PADs as critical cofactors in the initiation of skeletal muscle differentiation and reveals previously unappreciated connections between two major co-activator families during normal tissue development. Moreover, the results reveal important considerations for ongoing therapeutic approaches to myriad human diseases that utilize inhibitors of each enzyme family.