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Mechanisms governing interaction of the chromosomal protein SMCHD1 with chromatin determined by live-cell and single molecule imaging

ABSTRACT: The chromosomal protein SMCHD1 is a GHKL-ATPase that plays important roles in epigenetic silencing, including on the inactive X chromosome (Xi) and at the D4Z4 macrosatellite linked to regulation of DUX4 expression in the disorders FSHD2 and BAMS. In this study we use live-cell and single-molecule imaging approaches to investigate SMCHD1 interactions with chromatin and its function in epigenetic silencing. We show that chromatin binding of SMCHD1 genome wide, including on Xi, is critically dependent on the protein LRIF1 that mediates interaction with H3K9me2/3 modified nucleosomes. Using engineered mutations in the GHKL ATPase domain we show that ATP hydrolysis is required for SMCHD1 function on chromatin and gene silencing, but is dispensable for chromatin binding. A gain of function mutation, G137E, that occurs in BAMS patients, results in accelerated Xi recruitment and greater Xi chromosome compaction. Together, our findings advance mechanistic understanding of SMCHD1 function on Xi and at other target sites in the genome.

ORGANISM(S): Mus musculus

PROVIDER: GSE295772 | GEO | 2026/04/30

REPOSITORIES: GEO

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A proteomics study identifying interactors of the FSHD2 gene product SMCHD1 reveals RUVBL1-dependent DUX4 repression.

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Small noncoding RNAs in FSHD2 muscle cells reveal both DUX4- and SMCHD1-specific signatures

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Project description:Stable silencing of the inactive X chromosome (Xi) in female mammals is crucial for the development of embryos and their postnatal health. SmcHD1 is essential for stable silencing of the Xi, and its functional deficiency results in derepression of many X-inactivated genes. Although SmcHD1 has been suggested to play an important role in the formation of higher-order chromatin structure of the Xi, the underlying mechanism is largely unknown. Here, we explore the epigenetic state of the Xi in SmcHD1-deficient epiblast stem cells and mouse embryonic fibroblasts in comparison with their wild-type counterparts. The results suggest that SmcHD1 underlies the formation of H3K9me3-enriched blocks on the Xi, which, although the importance of H3K9me3 has been largely overlooked in mice, play a crucial role in the establishment of the stably silenced state. We propose that the H3K9me3 blocks formed on the Xi facilitate robust heterochromatin formation in combination with H3K27me3, and that the substantial loss of H3K9me3 caused by SmcHD1 deficiency leads to aberrant distribution of H3K27me3 on the Xi and derepression of X-inactivated genes.

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Project description:X chromosome inactivation involves multiple levels of chromatin modification, established progressively and in a stepwise manner during early development. The chromosomal protein Smchd1 has recently been shown to play an important role in DNA methylation of CpG islands (CGIs), a late step in the X inactivation pathway required for long-term stability of gene silencing. Here we show that inactive X chromosome (Xi) CGI methylation can occur via either Smchd1 dependent or independent pathways. Smchd1 dependent CGI methylation, the primary pathway, is acquired gradually over an extended period, whereas Smchd1 independent CGI methylation occurs rapidly after the onset of X inactivation. The de novo methyltransferase Dnmt3b is required for methylation of both classes of CGI, whereas Dnmt3a and Dnmt3L are dispensable. Xi CGIs methylated by these distinct pathways differ in respect to their sequence characteristics and immediate chromosomal environment. We discuss the implications of these results for understanding CGI methylation during development. Examination of CpG methylated DNA from wild type and smchd1 null male and female somatic cells and female ES cells differentiated for either 7 or 10 days. Duplicate samples of each type were generated.

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