Heterochromatin remodeling is critical for various cell processes. In particular, the “loss of heterochromatin” phenotype in cellular senescence is associated with the process of aging and age-related disorders. Although biological processes of senescent cells, including senescence-associated heterochromatin foci (SAHF) formation, chromosome compaction, and redistribution of key proteins, have been closely associated with high-order chromatin structure, the relationship between the high-order chromatin reorganization and the loss of heterochromatin phenotype during senescence has not been fully understood. By using senescent and deep senescent fibroblasts induced by DNA damage harboring the “loss of heterochromatin” phenotype, we observed progressive 3D reorganization of heterochromatin during senescence. Facultative and constitutive heterochromatin marked by H3K27me3 and H3K9me3, respectively, show different alterations. Facultative heterochromatin tends to switch from the repressive B-compartment to the active A-compartment, whereas constitutive heterochromatin shows no significant changes at the compartment level but enhanced interactions between themselves. Both types of heterochromatin show increased chromatin accessibility and gene expression leakage during senescence. Furthermore, increased chromatin accessibility in potential CTCF binding sites accompanies the establishment of novel loops in constitutive heterochromatin. Finally, we also observed aberrant expression of repetitive elements, including LTR (long terminal repeat) and satellite classes. Overall, facultative and constitutive heterochromatin show both similar and distinct multiscale alterations in the 3D map, chromatin accessibility, and gene expression leakage. This study provides an epigenomic map of heterochromatin reorganization during senescence.

中文翻译：

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异染色质的丢失与细胞衰老过程中的多尺度三维基因组重组和异常转录有关

异染色质重塑对于各种细胞过程至关重要。特别是，细胞衰老中的“异染色质丢失”表型与衰老过程和与年龄相关的疾病有关。尽管衰老细胞的生物学过程，包括衰老相关异染色质灶（SAHF）的形成、染色体压缩和关键蛋白的重新分布，与高阶染色质结构密切相关，但高阶染色质重组与丢失之间的关系衰老过程中异染色质表型的变化尚未完全了解。通过使用由具有“异染色质丢失”表型的 DNA 损伤诱导的衰老和深度衰老成纤维细胞，我们观察到了衰老过程中异染色质的渐进 3D 重组。分别由 H3K27me3 和 H3K9me3 标记的兼性和组成型异染色质显示出不同的改变。兼性异染色质倾向于从抑制性 B 区室转换到活性 A 区室，而组成型异染色质在区室水平上没有显着变化，但它们之间的相互作用增强。两种类型的异染色质在衰老过程中都表现出染色质可及性和基因表达泄漏的增加。此外，潜在 CTCF 结合位点中染色质可及性的增加伴随着组成型异染色质中新环的建立。最后，我们还观察到重复元件的异常表达，包括LTR（长末端重复）和卫星类。总体而言，兼性和组成性异染色质在 3D 图谱、染色质可及性和基因表达泄漏方面显示出相似和不同的多尺度变化。这项研究提供了衰老过程中异染色质重组的表观基因组图谱。