Group of Genetics and Epigenetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
Group of Computational Biology and Bioinformatics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
Sci Rep. 2021 Aug 30;11(1):17346. doi: 10.1038/s41598-021-96844-0.
Tumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the human MAGEA6/GABRA3 gene locus, we observed that DNA hypomethylation in tumor cells can lead to the activation of a long transcript (CT-GABRA3) that overlaps downstream promoters (GABRQ and GABRA3) and triggers their hypermethylation. Overlapped promoters displayed increases in H3K36me3, a histone mark deposited during transcriptional elongation and known to stimulate de novo DNA methylation. Consistent with such a processive mechanism, increases in H3K36me3 and DNA methylation were observed over the entire region covered by the CT-GABRA3 overlapping transcript. Importantly, experimental induction of CT-GABRA3 by depletion of DNMT1 DNA methyltransferase, resulted in a similar pattern of regional DNA hypermethylation. Bioinformatics analyses in lung cancer datasets identified other genomic loci displaying this process of coupled DNA hypo/hypermethylation, and some of these included tumor suppressor genes, e.g. RERG and PTPRO. Together, our work reveals that focal DNA hypomethylation in tumors can indirectly contribute to hypermethylation of nearby promoters through activation of overlapping transcription, and establishes therefore an unsuspected connection between these two opposite epigenetic alterations.
肿瘤的发生发展涉及 DNA 甲基化模式的改变，包括不同基因组区域的获得（高甲基化）和丢失（低甲基化）。这些两种相反但同时存在的肿瘤改变的机制尚不清楚。在研究人类 MAGEA6/GABRA3 基因座时，我们观察到肿瘤细胞中的 DNA 低甲基化可导致长转录本（CT-GABRA3）的激活，该转录本与下游启动子（GABRQ 和 GABRA3）重叠，并触发它们的高甲基化。重叠的启动子显示出 H3K36me3 的增加，这是一种在转录延伸过程中沉积的组蛋白标记，已知可刺激从头 DNA 甲基化。与这种连续的机制一致，在 CT-GABRA3 重叠转录本覆盖的整个区域都观察到 H3K36me3 和 DNA 甲基化的增加。重要的是，通过耗尽 DNMT1 DNA 甲基转移酶诱导 CT-GABRA3 的实验，导致整个区域的 DNA 超甲基化呈现出类似的模式。在肺癌数据集的生物信息学分析中，鉴定出其他显示这种偶联 DNA 低/高甲基化过程的基因组位点，其中一些包括肿瘤抑制基因，例如 RERG 和 PTPRO。总之，我们的工作表明，肿瘤中的局灶性 DNA 低甲基化可以通过激活重叠转录间接导致附近启动子的高甲基化，并因此建立了这两种相反的表观遗传改变之间的意外联系。
