DNA 超甲基化侵犯癌症中 CpG 岛边界是由 H3K4 单甲基化模式预先决定的。

DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns.

机构信息

Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; Developmental Epigenomics Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.

Immunogenomics Laboratory, Immunology Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.

出版信息

Cancer Cell. 2019 Feb 11;35(2):297-314.e8. doi: 10.1016/j.ccell.2019.01.004.

DOI:10.1016/j.ccell.2019.01.004

PMID:30753827

Abstract

Promoter CpG islands are typically unmethylated in normal cells, but in cancer a proportion are subject to hypermethylation. Using methylome sequencing we identified CpG islands that display partial methylation encroachment across the 5' or 3' CpG island borders. CpG island methylation encroachment is widespread in prostate and breast cancer and commonly associates with gene suppression. We show that the pattern of H3K4me1 at CpG island borders in normal cells predicts the different modes of cancer CpG island hypermethylation. Notably, genetic manipulation of Kmt2d results in concordant alterations in H3K4me1 levels and CpG island border DNA methylation encroachment. Our findings suggest a role for H3K4me1 in the demarcation of CpG island methylation borders in normal cells, which become eroded in cancer.

摘要

启动子 CpG 岛通常在正常细胞中是非甲基化的，但在癌症中，一部分会发生过度甲基化。我们使用甲基化组测序鉴定了在 5' 或 3' CpG 岛边界处显示部分甲基化侵犯的 CpG 岛。CpG 岛甲基化侵犯在前列腺癌和乳腺癌中广泛存在，通常与基因抑制有关。我们表明，正常细胞中 CpG 岛边界处 H3K4me1 的模式可预测癌症 CpG 岛过度甲基化的不同模式。值得注意的是，Kmt2d 的遗传操作导致 H3K4me1 水平和 CpG 岛边界 DNA 甲基化侵犯的一致改变。我们的发现表明 H3K4me1 在正常细胞中 CpG 岛甲基化边界的划定中发挥作用，而在癌症中，这些边界会被侵蚀。