SMCHD1 maintains heterochromatin, genome compartments and epigenome landscape in human myoblasts

Zhijun Huang, Wei Cui, Ishara Ratnayake, Kristin L. Gallik, Lorna Cohen, Rabi Tawil and Gerd P. Pfeifer ()
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Zhijun Huang: Van Andel Institute
Wei Cui: Van Andel Institute
Ishara Ratnayake: Van Andel Institute
Kristin L. Gallik: Van Andel Institute
Lorna Cohen: Van Andel Institute
Rabi Tawil: University of Rochester Medical Center
Gerd P. Pfeifer: Van Andel Institute

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Mammalian genomes are subdivided into euchromatic A compartments that contain mostly active chromatin, and inactive, heterochromatic B compartments. However, it is not well understood how A and B genome compartments are established and maintained. Here we study SMCHD1, an SMC-like protein best known for its role in X chromosome inactivation, in human male myoblasts. SMCHD1 colocalizes with Lamin B1 and the heterochromatin mark H3K9me3. Loss of SMCHD1 leads to extensive heterochromatin and Lamin B1 depletion at the nuclear lamina, acquisition of active chromatin states and increased DNA methylation along chromosomes. In absence of SMCHD1, long range intra-chromosomal contacts between B compartments are lost while many new TADs and loops are formed. Inactivation of SMCHD1 promotes numerous B to A compartment transitions accompanied by activation of silenced genes. The data suggests that SMCHD1 functions as an anchor for heterochromatin domains at the nuclear lamina ensuring that these domains are poorly accessible to DNA methyltransferases and to epigenome modification enzymes that typically operate in active chromatin. Thus, the properties of SMCHD1 in heterochromatin maintenance extend well beyond its role in X chromosome inactivation.

Date: 2025
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DOI: 10.1038/s41467-025-62211-0

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