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

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

Author information

1
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.
2
Immunogenomics Laboratory, Immunology Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
3
Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia.
4
Immunogenomics Laboratory, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
5
Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2010, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2010, Australia; Cancer Division, The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia.
6
Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York 10021, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York 10065, USA; Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York 10065, USA; Department for Biomedical Research, University of Bern, Bern, CH-3012, Switzerland; Bern Center for Precision Medicine, Inselspital, Bern University Hospital, Bern, CH-3012, Switzerland.
7
Sydney Medical School, University of Sydney, Sydney, NSW 2010, Australia; St Vincent's Clinical School, UNSW, Sydney, NSW 2010, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW 2050, Australia; Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia; Cancer Division, The Kinghorn Cancer Centre, Sydney, NSW 2010, Australia.
8
St Vincent's Clinical School, UNSW, Sydney, NSW 2010, Australia; Developmental Epigenomics Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
9
Department of Anatomy & Developmental Biology, Monash University, Melbourne, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Melbourne, VIC 3800, Australia; Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC 3800, Australia.
10
Immunogenomics Laboratory, Immunology Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, UNSW, Sydney, NSW 2010, Australia.
11
Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; St Vincent's Clinical School, UNSW, Sydney, NSW 2010, Australia. Electronic address: c.stirzaker@garvan.org.au.
12
Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; St Vincent's Clinical School, UNSW, Sydney, NSW 2010, Australia. Electronic address: s.clark@garvan.org.au.

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.

KEYWORDS:

5-hydroxymethylation; BisChIP-seq; CpG islands; DNA methylation encroachment; H3K4 monomethylation; TAB-seq; WGBS; cancer; hypermethylation

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