Huang Zhijun, Cui Wei, Ratnayake Ishara, Gallik Kristin L, Cohen Lorna, Tawil Rabi, Pfeifer Gerd P
Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan, USA.
Cryo-EM Core, Van Andel Institute, Grand Rapids, Michigan, USA.
Nat Commun. 2025 Jul 26;16(1):6900. doi: 10.1038/s41467-025-62211-0.
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.
哺乳动物基因组被细分为常染色质的A区室，其主要包含活性染色质，以及非活性的异染色质B区室。然而，目前对于A和B基因组区室是如何建立和维持的还了解甚少。在这里，我们在人类雄性成肌细胞中研究了SMCHD1，一种以其在X染色体失活中的作用而闻名的SMC样蛋白。SMCHD1与核纤层蛋白B1和异染色质标记H3K9me3共定位。SMCHD1的缺失导致核纤层处广泛的异染色质和核纤层蛋白B1缺失，获得活性染色质状态并增加沿染色体的DNA甲基化。在没有SMCHD1的情况下，B区室之间的长距离染色体内接触丧失，同时形成了许多新的拓扑相关结构域（TAD）和环。SMCHD1的失活促进了大量B区室向A区室的转变，并伴随着沉默基因的激活。数据表明，SMCHD1作为核纤层处异染色质结构域的锚定物，确保这些结构域难以被DNA甲基转移酶和通常在活性染色质中起作用的表观基因组修饰酶所接近。因此，SMCHD1在异染色质维持中的特性远远超出了其在X染色体失活中的作用。
