SUMOylation differentially regulates SMCHD1 complex formation and function in a genomic context-specific manner

Structural Maintenance of Chromosomes Hinge Domain Containing 1 (SMCHD1) is a chromatin repressor regulating gene expression and chromatin architecture of distinct autosomal and X-chromosomal loci. SMCHD1 mutations cause derepression of the D4Z4 macrosatellite repeat-embedded DUX4 gene in skeletal muscle of facioscapulohumeral muscular dystrophy (FSHD) patients Little is known about the regulation and post-translational modification of SMCHD1. Here we report the SUMOylation dynamics of SMCHD1 and its impact on autosomal single copy and repetitive loci, and the inactive X chromosome (Xi).

We identify that SMCHD1 is SUMOylated primarily at lysine 1374, uncover factors regulating SMCHD1 SUMOylation, and demonstrate that SMCHD1 interacts with chromatin repressors TRIM28, HNRNPK and SETDB1 in a SUMO-dependent manner. We find that SUMOylation impacts Xi engagement of SMCHD1, maintenance of a repressive D4Z4 chromatin structure preventing DUX4 expression, and regulation of LRIF1 promoter activity. The rapid, SUMO-dependent upregulation of DUX4 could explain the bursts of DUX4 expression typical for FSHD muscle.