美国哈佛大学Daniel A. Haber等研究人员合作发现，DNA低甲基化沉默早期前列腺癌和CTC中的抗肿瘤免疫基因。相关论文于2023年6月15日在线发表在《细胞》杂志上。
通过高分辨率的全基因组单细胞DNA甲基化测序，研究人员确定了40个核心域，这些域从前列腺恶性肿瘤的最早可检测阶段到转移性循环肿瘤细胞（CTC）都一致地被低甲基化。嵌套在这些抑制域中的是保留甲基化的较小位点，它们逃脱了沉默，并富含细胞增殖基因。核心低甲基化区域内的转录沉默基因富含免疫相关基因；其中最突出的是一个包含所有五个CD1基因的单一基因簇，这些基因向NKT细胞提供脂质抗原，以及四个与IFI16相关的干扰素诱导基因，涉及先天免疫。
在具有免疫能力的小鼠中重新表达CD1或IFI16的小鼠直系同源物，可以废除肿瘤的发生，并伴随着抗肿瘤免疫力的激活。因此，早期的表观遗传学变化可能塑造了肿瘤的发生，针对的是确定的染色体位点内的共定位基因。在富含CTC的血液标本中可以检测到低甲基化域。
据悉，癌症的特点是与低甲基化相关的大型染色质域的沉默，其对肿瘤发生的贡献尚不确定。
附：英文原文
Title: DNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs
Author: Hongshan Guo, Joanna A. Vuille, Ben S. Wittner, Emily M. Lachtara, Yu Hou, Maoxuan Lin, Ting Zhao, Ayush T. Raman, Hunter C. Russell, Brittany A. Reeves, Haley M. Pleskow, Chin-Lee Wu, Andreas Gnirke, Alexander Meissner, Jason A. Efstathiou, Richard J. Lee, Mehmet Toner, Martin J. Aryee, Michael S. Lawrence, David T. Miyamoto, Shyamala Maheswaran, Daniel A. Haber
Issue&Volume: 2023-06-15
Abstract: Cancer is characterized by hypomethylation-associated silencing of large chromatin domains, whose contribution to tumorigenesis is uncertain. Through high-resolution genome-wide single-cell DNA methylation sequencing, we identify 40 core domains that are uniformly hypomethylated from the earliest detectable stages of prostate malignancy through metastatic circulating tumor cells (CTCs). Nested among these repressive domains are smaller loci with preserved methylation that escape silencing and are enriched for cell proliferation genes. Transcriptionally silenced genes within the core hypomethylated domains are enriched for immune-related genes; prominent among these is a single gene cluster harboring all five CD1 genes that present lipid antigens to NKT cells and four IFI16-related interferon-inducible genes implicated in innate immunity. The re-expression of CD1 or IFI16 murine orthologs in immuno-competent mice abrogates tumorigenesis, accompanied by the activation of anti-tumor immunity. Thus, early epigenetic changes may shape tumorigenesis, targeting co-located genes within defined chromosomal loci. Hypomethylation domains are detectable in blood specimens enriched for CTCs.
DOI: 10.1016/j.cell.2023.05.028
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00580-9