Liang Yuan, Liu Mengni, Liu Bingyuan, Ziman Benjamin, Peng Guanjie, Mao Qiong, Wang Xingzhe, Jiang Lizhen, Lin De-Chen, Zheng Yueyuan
Clinical Big Data Research Center, Scientific Research Center, Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, People's Republic of China.
Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, and Norris Comprehensive Cancer Center, University of Southern California, 2250 Alcazar Street - CSA 207D, Los Angeles, CA, 90033, USA.
Epigenetics Chromatin. 2025 Jan 20;18(1):6. doi: 10.1186/s13072-025-00570-0.
Histone modification H3K27me3 plays a critical role in normal development and is associated with various diseases, including cancer. This modification forms large chromatin domains, known as Large Organized Chromatin Lysine Domains (LOCKs), which span several hundred kilobases.
In this study, we identify and categorize H3K27me3 LOCKs in 109 normal human samples, distinguishing between long and short LOCKs. Our findings reveal that long LOCKs are predominantly associated with developmental processes, while short LOCKs are enriched in poised promoters and are most associated with low gene expression. Further analysis of LOCKs in different DNA methylation contexts shows that long LOCKs are primarily located in partially methylated domains (PMDs), particularly in short-PMDs, where they are most likely responsible for the low expressions of oncogenes. We observe that in cancer cell lines, including those from esophageal and breast cancer, long LOCKs shift from short-PMDs to intermediate-PMDs and long-PMDs. Notably, a significant subset of tumor-associated long LOCKs in intermediate- and long-PMDs exhibit reduced H3K9me3 levels, suggesting that H3K27me3 compensates for the loss of H3K9me3 in tumors. Additionally, we find that genes upregulated in tumors following the loss of short LOCKs are typically poised promoter genes in normal cells, and their transcription is regulated by the ETS1 transcription factor.
These results provide new insights into the role of H3K27me3 LOCKs in cancer and underscore their potential impact on epigenetic regulation and disease mechanisms.
组蛋白修饰H3K27me3在正常发育中起关键作用，并与包括癌症在内的多种疾病相关。这种修饰形成了被称为大的有组织染色质赖氨酸结构域（LOCKs）的大型染色质结构域，其跨度可达数百千碱基。
在本研究中，我们在109个正常人类样本中鉴定并分类了H3K27me3 LOCKs，区分了长LOCKs和短LOCKs。我们的研究结果表明，长LOCKs主要与发育过程相关，而短LOCKs在准备就绪的启动子中富集，并且与低基因表达最为相关。对不同DNA甲基化背景下的LOCKs进行进一步分析表明，长LOCKs主要位于部分甲基化结构域（PMDs），特别是短PMDs中，在那里它们最有可能导致癌基因的低表达。我们观察到，在癌细胞系中，包括来自食管癌和乳腺癌的细胞系，长LOCKs从短PMDs转移到中等PMDs和长PMDs。值得注意的是，中等和长PMDs中与肿瘤相关的长LOCKs的一个重要子集显示H3K9me3水平降低，这表明H3K27me3补偿了肿瘤中H3K9me3的缺失。此外，我们发现，在短LOCKs缺失后肿瘤中上调的基因通常是正常细胞中准备就绪的启动子基因，并且它们的转录受ETS1转录因子调控。
这些结果为H3K27me3 LOCKs在癌症中的作用提供了新的见解，并强调了它们对表观遗传调控和疾病机制的潜在影响。
