Sun Wenjing, Wang Jiacheng, Liu Wenqian, Tang Baixue, Qu Hongyuan, Su Huanxing, Wang Jianwei, Li Haitao, Xie Wei, Li Pilong
State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.
Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.
Cell Rep. 2025 Jul 22;44(7):116003. doi: 10.1016/j.celrep.2025.116003. Epub 2025 Jul 11.
Eukaryotic chromatin is organized into compartments for gene expression regulation, but the underlying mechanisms remain unclear. Here, we demonstrate that multivalent H3K27me3 and its reader, the CBX7-PRC1 complex, regulate facultative heterochromatin via a phase separation mechanism. Facultative and constitutive heterochromatin represent distinct, coexisting condensates in nuclei. In vitro, H3K27me3- and H3K9me3-marked nucleosomal arrays and their reader complexes can phase separate into immiscible condensates that are analogous to the relationship between facultative and constitutive heterochromatin in vivo. Moreover, overexpression of CBX7-PRC1 causes aberrant chromatin compartmentalization as demonstrated by H3K9me3 CUT&Tag and up-regulation of genes related to cancer, such as acute myeloblastic leukemia (AML). Chromobox 7 (CBX7) inhibitor effectively inhibits cancer cell proliferation, possibly through phase-separation-mediated compartment reorganization. Our data demonstrate how the specificity of compartmentalization is achieved based on the formation of immiscible phase-separated condensates and offer potential epigenetic mechanistic insights into tumor development.
真核染色质被组织成不同的区域用于基因表达调控，但其潜在机制仍不清楚。在这里，我们证明多价的H3K27me3及其读取器CBX7-PRC1复合物通过相分离机制调节兼性异染色质。兼性和组成型异染色质在细胞核中代表不同的、共存的凝聚物。在体外，H3K27me3和H3K9me3标记的核小体阵列及其读取器复合物可以相分离成不混溶的凝聚物，这类似于体内兼性和组成型异染色质之间的关系。此外，如H3K9me3 CUT&Tag所示，CBX7-PRC1的过表达会导致异常的染色质区室化，并上调与癌症相关的基因，如急性髓性白血病（AML）。Chromobox 7（CBX7）抑制剂可能通过相分离介导的区室重组有效抑制癌细胞增殖。我们的数据证明了基于不混溶的相分离凝聚物的形成如何实现区室化的特异性，并为肿瘤发展提供了潜在的表观遗传机制见解。
