5-hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer

Santiago Uribe-lewis, Rory Stark, Thomas Carroll, Mark J Dunning, Martin Bachman, Yoko Ito, Lovorka Stojic, Silvia Halim, Sarah L Vowler, Andy G Lynch, Benjamin Delatte, Eric J De Bony, Laurence Colin, Matthieu Defrance, Felix Krueger, Ana-luisa Silva, Rogier Ten Hoopen, Ashraf Ek Ibrahim, François Fuks, Adele Murrell

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

BACKGROUND:
The discovery of cytosine hydroxymethylation (5hmC) as a mechanism that potentially controls DNA methylation changes typical of neoplasia prompted us to investigate its behaviour in colon cancer. 5hmC is globally reduced in proliferating cells such as colon tumours and the gut crypt progenitors, from which tumours can arise.
RESULTS:
Here, we show that colorectal tumours and cancer cells express Ten-Eleven-Translocation (TET) transcripts at levels similar to normal tissues. Genome-wide analyses show that promoters marked by 5hmC in normal tissue, and those identified as TET2 targets in colorectal cancer cells, are resistant to methylation gain in cancer. In vitro studies of TET2 in cancer cells confirm that these promoters are resistant to methylation gain independently of sustained TET2 expression. We also find that a considerable number of the methylation gain-resistant promoters marked by 5hmC in normal colon overlap with those that are marked with poised bivalent histone modifications in embryonic stem cells.
CONCLUSIONS:
Together our results indicate that promoters that acquire 5hmC upon normal colon differentiation are innately resistant to neoplastic hypermethylation by mechanisms that do not require high levels of 5hmC in tumours. Our study highlights the potential of cytosine modifications as biomarkers of cancerous cell proliferation.
Original languageEnglish
Article number69
Pages (from-to)1-15
Number of pages15
JournalGenome Biology
Volume16
Issue number1
DOIs
Publication statusPublished - 1 Apr 2015

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colon
methylation
cancer
Colon
colorectal neoplasms
tumor
promoter regions
DNA
neoplasms
Methylation
cytosine
Colorectal Neoplasms
Neoplasms
Cytosine
Histone Code
embryonic stem cells
DNA methylation
histones
in vitro studies
translocation

Cite this

Uribe-lewis, S., Stark, R., Carroll, T., Dunning, M. J., Bachman, M., Ito, Y., ... Murrell, A. (2015). 5-hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer. Genome Biology, 16(1), 1-15. [69]. https://doi.org/10.1186/s13059-015-0605-5

5-hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer. / Uribe-lewis, Santiago; Stark, Rory; Carroll, Thomas; Dunning, Mark J; Bachman, Martin; Ito, Yoko; Stojic, Lovorka; Halim, Silvia; Vowler, Sarah L; Lynch, Andy G; Delatte, Benjamin; De Bony, Eric J; Colin, Laurence; Defrance, Matthieu; Krueger, Felix; Silva, Ana-luisa; Ten Hoopen, Rogier; Ibrahim, Ashraf Ek; Fuks, François; Murrell, Adele.

In: Genome Biology, Vol. 16, No. 1, 69, 01.04.2015, p. 1-15.

Research output: Contribution to journalArticle

Uribe-lewis, S, Stark, R, Carroll, T, Dunning, MJ, Bachman, M, Ito, Y, Stojic, L, Halim, S, Vowler, SL, Lynch, AG, Delatte, B, De Bony, EJ, Colin, L, Defrance, M, Krueger, F, Silva, A, Ten Hoopen, R, Ibrahim, AE, Fuks, F & Murrell, A 2015, '5-hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer', Genome Biology, vol. 16, no. 1, 69, pp. 1-15. https://doi.org/10.1186/s13059-015-0605-5
Uribe-lewis S, Stark R, Carroll T, Dunning MJ, Bachman M, Ito Y et al. 5-hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer. Genome Biology. 2015 Apr 1;16(1):1-15. 69. https://doi.org/10.1186/s13059-015-0605-5
Uribe-lewis, Santiago ; Stark, Rory ; Carroll, Thomas ; Dunning, Mark J ; Bachman, Martin ; Ito, Yoko ; Stojic, Lovorka ; Halim, Silvia ; Vowler, Sarah L ; Lynch, Andy G ; Delatte, Benjamin ; De Bony, Eric J ; Colin, Laurence ; Defrance, Matthieu ; Krueger, Felix ; Silva, Ana-luisa ; Ten Hoopen, Rogier ; Ibrahim, Ashraf Ek ; Fuks, François ; Murrell, Adele. / 5-hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer. In: Genome Biology. 2015 ; Vol. 16, No. 1. pp. 1-15.
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AU - Stark, Rory

AU - Carroll, Thomas

AU - Dunning, Mark J

AU - Bachman, Martin

AU - Ito, Yoko

AU - Stojic, Lovorka

AU - Halim, Silvia

AU - Vowler, Sarah L

AU - Lynch, Andy G

AU - Delatte, Benjamin

AU - De Bony, Eric J

AU - Colin, Laurence

AU - Defrance, Matthieu

AU - Krueger, Felix

AU - Silva, Ana-luisa

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AU - Ibrahim, Ashraf Ek

AU - Fuks, François

AU - Murrell, Adele

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N2 - BACKGROUND:The discovery of cytosine hydroxymethylation (5hmC) as a mechanism that potentially controls DNA methylation changes typical of neoplasia prompted us to investigate its behaviour in colon cancer. 5hmC is globally reduced in proliferating cells such as colon tumours and the gut crypt progenitors, from which tumours can arise.RESULTS:Here, we show that colorectal tumours and cancer cells express Ten-Eleven-Translocation (TET) transcripts at levels similar to normal tissues. Genome-wide analyses show that promoters marked by 5hmC in normal tissue, and those identified as TET2 targets in colorectal cancer cells, are resistant to methylation gain in cancer. In vitro studies of TET2 in cancer cells confirm that these promoters are resistant to methylation gain independently of sustained TET2 expression. We also find that a considerable number of the methylation gain-resistant promoters marked by 5hmC in normal colon overlap with those that are marked with poised bivalent histone modifications in embryonic stem cells.CONCLUSIONS:Together our results indicate that promoters that acquire 5hmC upon normal colon differentiation are innately resistant to neoplastic hypermethylation by mechanisms that do not require high levels of 5hmC in tumours. Our study highlights the potential of cytosine modifications as biomarkers of cancerous cell proliferation.

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