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

Ksenia Skvortsova, Etienne Masle-Farquhar, Phuc Loi Luu, Jenny Z. Song, Wenjia Qu, Elena Zotenko, Cathryn M. Gould, Qian Du, Timothy J. Peters, Yolanda Colino-Sanguino, Ruth Pidsley, Shalima S. Nair, Amanda Khoury, Grady C. Smith, Lisa A. Miosge, Joanne H. Reed, James G. Kench, Mark A. Rubin, Lisa Horvath, Ozren Bogdanovic & 5 others Sue Mei Lim, Jose M. Polo, Christopher C. Goodnow, Clare Stirzaker, Susan J. Clark

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)297-314
Number of pages18
JournalCancer Cell
Volume35
Issue number2
DOIs
Publication statusPublished - 11 Feb 2019

Keywords

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

Cite this

Skvortsova, K., Masle-Farquhar, E., Luu, P. L., Song, J. Z., Qu, W., Zotenko, E., ... Clark, S. J. (2019). DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns. Cancer Cell, 35(2), 297-314. https://doi.org/10.1016/j.ccell.2019.01.004
Skvortsova, Ksenia ; Masle-Farquhar, Etienne ; Luu, Phuc Loi ; Song, Jenny Z. ; Qu, Wenjia ; Zotenko, Elena ; Gould, Cathryn M. ; Du, Qian ; Peters, Timothy J. ; Colino-Sanguino, Yolanda ; Pidsley, Ruth ; Nair, Shalima S. ; Khoury, Amanda ; Smith, Grady C. ; Miosge, Lisa A. ; Reed, Joanne H. ; Kench, James G. ; Rubin, Mark A. ; Horvath, Lisa ; Bogdanovic, Ozren ; Lim, Sue Mei ; Polo, Jose M. ; Goodnow, Christopher C. ; Stirzaker, Clare ; Clark, Susan J. / DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns. In: Cancer Cell. 2019 ; Vol. 35, No. 2. pp. 297-314.
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title = "DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns",
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, cancer, CpG islands, DNA methylation encroachment, H3K4 monomethylation, hypermethylation, TAB-seq, WGBS",
author = "Ksenia Skvortsova and Etienne Masle-Farquhar and Luu, {Phuc Loi} and Song, {Jenny Z.} and Wenjia Qu and Elena Zotenko and Gould, {Cathryn M.} and Qian Du and Peters, {Timothy J.} and Yolanda Colino-Sanguino and Ruth Pidsley and Nair, {Shalima S.} and Amanda Khoury and Smith, {Grady C.} and Miosge, {Lisa A.} and Reed, {Joanne H.} and Kench, {James G.} and Rubin, {Mark A.} and Lisa Horvath and Ozren Bogdanovic and Lim, {Sue Mei} and Polo, {Jose M.} and Goodnow, {Christopher C.} and Clare Stirzaker and Clark, {Susan J.}",
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Skvortsova, K, Masle-Farquhar, E, Luu, PL, Song, JZ, Qu, W, Zotenko, E, Gould, CM, Du, Q, Peters, TJ, Colino-Sanguino, Y, Pidsley, R, Nair, SS, Khoury, A, Smith, GC, Miosge, LA, Reed, JH, Kench, JG, Rubin, MA, Horvath, L, Bogdanovic, O, Lim, SM, Polo, JM, Goodnow, CC, Stirzaker, C & Clark, SJ 2019, 'DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns' Cancer Cell, vol. 35, no. 2, pp. 297-314. https://doi.org/10.1016/j.ccell.2019.01.004

DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns. / Skvortsova, Ksenia; Masle-Farquhar, Etienne; Luu, Phuc Loi; Song, Jenny Z.; Qu, Wenjia; Zotenko, Elena; Gould, Cathryn M.; Du, Qian; Peters, Timothy J.; Colino-Sanguino, Yolanda; Pidsley, Ruth; Nair, Shalima S.; Khoury, Amanda; Smith, Grady C.; Miosge, Lisa A.; Reed, Joanne H.; Kench, James G.; Rubin, Mark A.; Horvath, Lisa; Bogdanovic, Ozren; Lim, Sue Mei; Polo, Jose M.; Goodnow, Christopher C.; Stirzaker, Clare; Clark, Susan J.

In: Cancer Cell, Vol. 35, No. 2, 11.02.2019, p. 297-314.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns

AU - Skvortsova, Ksenia

AU - Masle-Farquhar, Etienne

AU - Luu, Phuc Loi

AU - Song, Jenny Z.

AU - Qu, Wenjia

AU - Zotenko, Elena

AU - Gould, Cathryn M.

AU - Du, Qian

AU - Peters, Timothy J.

AU - Colino-Sanguino, Yolanda

AU - Pidsley, Ruth

AU - Nair, Shalima S.

AU - Khoury, Amanda

AU - Smith, Grady C.

AU - Miosge, Lisa A.

AU - Reed, Joanne H.

AU - Kench, James G.

AU - Rubin, Mark A.

AU - Horvath, Lisa

AU - Bogdanovic, Ozren

AU - Lim, Sue Mei

AU - Polo, Jose M.

AU - Goodnow, Christopher C.

AU - Stirzaker, Clare

AU - Clark, Susan J.

PY - 2019/2/11

Y1 - 2019/2/11

N2 - 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.

AB - 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.

KW - 5-hydroxymethylation

KW - BisChIP-seq

KW - cancer

KW - CpG islands

KW - DNA methylation encroachment

KW - H3K4 monomethylation

KW - hypermethylation

KW - TAB-seq

KW - WGBS

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DO - 10.1016/j.ccell.2019.01.004

M3 - Article

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JO - Cancer Cell

JF - Cancer Cell

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