Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Nat Commun. 2022 Jul 20;13(1):4199. doi: 10.1038/s41467-022-31857-5.
The genome can be divided into two spatially segregated compartments, A and B, which partition active and inactive chromatin states. While constitutive heterochromatin is predominantly located within the B compartment near the nuclear lamina, facultative heterochromatin marked by H3K27me3 spans both compartments. How epigenetic modifications, compartmentalization, and lamina association collectively maintain heterochromatin architecture remains unclear. Here we develop Lamina-Inducible Methylation and Hi-C (LIMe-Hi-C) to jointly measure chromosome conformation, DNA methylation, and lamina positioning. Through LIMe-Hi-C, we identify topologically distinct sub-compartments with high levels of H3K27me3 and differing degrees of lamina association. Inhibition of Polycomb repressive complex 2 (PRC2) reveals that H3K27me3 is essential for sub-compartment segregation. Unexpectedly, PRC2 inhibition promotes lamina association and constitutive heterochromatin spreading into H3K27me3-marked B sub-compartment regions. Consistent with this repositioning, genes originally marked with H3K27me3 in the B compartment, but not the A compartment, remain largely repressed, suggesting that constitutive heterochromatin spreading can compensate for H3K27me3 loss at a transcriptional level. These findings demonstrate that Polycomb sub-compartments and their antagonism with lamina association are fundamental features of genome structure. More broadly, by jointly measuring nuclear position and Hi-C contacts, our study demonstrates how compartmentalization and lamina association represent distinct but interdependent modes of heterochromatin regulation.
基因组可分为两个空间分隔的区室 A 和 B，它们分隔活跃和不活跃的染色质状态。虽然组成性异染色质主要位于靠近核层的 B 区室中，但是由 H3K27me3 标记的兼性异染色质跨越两个区室。然而，组蛋白修饰、区室化和核层关联如何共同维持异染色质结构仍然不清楚。在这里，我们开发了 Lamina-Inducible Methylation 和 Hi-C（LIMe-Hi-C）来联合测量染色体构象、DNA 甲基化和核层定位。通过 LIMe-Hi-C，我们确定了拓扑上不同的亚区室，这些亚区室具有高水平的 H3K27me3 和不同程度的核层关联。抑制多梳抑制复合物 2（PRC2）表明 H3K27me3 对于亚区室的分离是必不可少的。出乎意料的是，PRC2 抑制促进了核层关联和组成性异染色质扩散到 H3K27me3 标记的 B 亚区室区域。这种重定位与以下情况一致，即最初在 B 区室而不是 A 区室标记有 H3K27me3 的基因仍然主要受到抑制，这表明组成性异染色质的扩散可以在转录水平上弥补 H3K27me3 的缺失。这些发现表明，多梳亚区室及其与核层关联的拮抗作用是基因组结构的基本特征。更广泛地说，通过联合测量核位置和 Hi-C 接触，我们的研究表明区室化和核层关联如何代表异染色质调节的不同但相互依存的模式。
