SMCHD1 controls the structure and accessibility of heterochromatin and functions as an organizer of genome compartments (DamID-Seq)

Structural Maintenance of Chromosomes flexible Hinge Domain containing 1 (SMCHD1) is an SMC-like protein that plays an important role in X chromosome inactivation and is mutated in two human diseases, a muscular dystrophy, and a rare developmental disorder. Here we characterized the function of SMCHD1 in human myoblasts and focused on its role on autosomes. We found that SMCHD1 colocalizes with Lamin B1 and the constitutive heterochromatin mark H3K9me3. Loss of SMCHD1 leads to a loss of heterochromatin at nuclear lamina regions and to extensive changes of the epigenome on most chromosomes. In SMCHD1-deficient cells, about half the regions that normally bind SMCHD1 loose H3K9me3, acquire long stretches of DNA hypermethylation and gain a variety of active chromatin marks including H3K4me3, H3K4me1, histone H3K27 acetylation, and H3K36 di- and trimethylation. Three-dimensional chromatin analysis using HiC shows that long range contacts between different heterochromatin blocks (B compartments) on the same chromosome are diminished while there is extensive formation of new topologically associated domains (TADs) and loops anchored at newly created CTCF/RAD21 binding sites. Inactivation of SMCHD1 promotes many inactive (B) to active (A) compartment transitions. These transitions are accompanied by activation of about 200 previously silenced genes with potential implications for the etiology and progression of SMCHD1-linked diseases. Our data suggest that SMCHD1 functions as a genome compartment organizer and as an important anchor for heterochromatin domains at the nuclear lamina ensuring that lamina- associated domains are protected from histone and DNA modification enzymes that typically operate in active chromatin.