Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA, 92093-0359, USA.
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, 92093-0359, USA.
Nat Commun. 2022 Sep 8;13(1):5281. doi: 10.1038/s41467-022-32911-y.
The 3D genome has been shown to be organized into modules including topologically associating domains (TADs) and compartments that are primarily defined by spatial contacts from Hi-C. There exists a gap to investigate whether and how the spatial modularity of the chromatin is related to the functional modularity resulting from chromatin activity. Despite histone modifications reflecting chromatin activity, inferring spatial modularity of the genome directly from the histone modification patterns has not been well explored. Here, we report that histone modifications show a modular pattern (referred to as regulation associated modules, RAMs) that reflects spatial chromatin modularity. Enhancer-promoter interactions, loop anchors, super-enhancer clusters and extrachromosomal DNAs (ecDNAs) are found to occur more often within the same RAMs than within the same TADs. Consistently, compared to the TAD boundaries, deletions of RAM boundaries perturb the chromatin structure more severely (may even cause cell death) and somatic variants in cancer samples are more enriched in RAM boundaries. These observations suggest that RAMs reflect a modular organization of the 3D genome at a scale better aligned with chromatin activity, providing a bridge connecting the structural and functional modularity of the genome.
三维基因组被组织成模块，包括拓扑关联域（TAD）和隔室，这些主要是由 Hi-C 的空间接触定义的。目前还存在一个空白，需要研究染色质的空间模块化是否以及如何与染色质活性产生的功能模块化相关。尽管组蛋白修饰反映了染色质活性，但直接从组蛋白修饰模式推断基因组的空间模块化尚未得到充分探索。在这里，我们报告说，组蛋白修饰呈现出一种模块化模式（称为与调节相关的模块，RAMs），反映了空间染色质模块化。发现增强子-启动子相互作用、环锚、超级增强子簇和染色体外 DNA（ecDNA）在同一 RAM 内比在同一 TAD 内更频繁地发生。一致地，与 TAD 边界相比，RAM 边界的缺失更严重地扰乱了染色质结构（甚至可能导致细胞死亡），并且癌症样本中的体细胞变异在 RAM 边界中更为丰富。这些观察结果表明，RAMs 反映了三维基因组在与染色质活性更好对齐的尺度上的模块化组织，为连接基因组的结构和功能模块化提供了桥梁。
