Department of Advanced Bioscience, Graduate School of Agriculture, Kindai University, Nara 631-8505, Japan.
Department of Biological Science, Graduate School of Science, Osaka University, Toyonaka 560-0043, Japan.
Development. 2022 Aug 1;149(15). doi: 10.1242/dev.200864. Epub 2022 Aug 2.
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.
雌性哺乳动物中失活 X 染色体 (Xi) 的稳定沉默对于胚胎发育及其出生后的健康至关重要。SmcHD1 对于 Xi 的稳定沉默是必不可少的，其功能缺陷导致许多 X 失活基因的去抑制。尽管 SmcHD1 被认为在 Xi 的高级染色质结构形成中发挥重要作用，但潜在的机制在很大程度上尚不清楚。在这里，我们比较了 SmcHD1 缺陷的上胚层干细胞和小鼠胚胎成纤维细胞与野生型细胞中 Xi 的表观遗传状态。结果表明，SmcHD1 是 Xi 上富含 H3K9me3 块形成的基础，尽管 H3K9me3 在小鼠中的重要性在很大程度上被忽视，但它在建立稳定沉默状态中起着关键作用。我们提出，Xi 上形成的 H3K9me3 块与 H3K27me3 一起促进了强大的异染色质形成，而 SmcHD1 缺陷导致的 H3K9me3 的大量丢失导致 H3K27me3 在 Xi 上的异常分布和 X 失活基因的去抑制。
