5-hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer
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- 作者：Santiago Uribe-Lewis (1)
Rory Stark (1)
Thomas Carroll (1)
Mark J Dunning (1)
Martin Bachman (1)
Yoko Ito (1)
Lovorka Stojic (1)
Silvia Halim (1)
Sarah L Vowler (1)
Andy G Lynch (1)
Benjamin Delatte (2)
Eric J de Bony (2)
Laurence Colin (2)
Matthieu Defrance (2)
Felix Krueger (3)
Ana-Luisa Silva (4)
Rogier ten Hoopen (4)
Ashraf EK Ibrahim (4)
Fran莽ois Fuks (2)
Adele Murrell (1) (5)
1. Cancer Research UK Cambridge Institute ; University of Cambridge ; Robinson Way ; Cambridge ; CB2 0RE ; UK
2. Laboratory of Cancer Epigenetics ; Universit茅 Libre de Bruxelles ; Faculty of Medicine ; Route de Lennik 808 ; 1070 ; Brussels ; Belgium
3. Bioinformatics Group ; The Babraham Institute ; Babraham Research Campus ; Cambridge ; CB22 3AT ; UK
4. Department of Pathology ; Addenbrooke鈥檚 Hospital ; Box 231 ; Level 3 ; Hills Road ; Cambridge ; CB2 0QQ ; UK
5. Department of Biology and Biochemistry ; Centre for Regenerative Medicine ; University of Bath ; Claverton Down ; Bath ; BA2 7AY ; UK - 刊名：Genome Biology
- 出版年：2015
- 出版时间：December 2015
- 年：2015
- 卷：16
- 期：1
- 全文大小：2,541 KB
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- 出版者：BioMed Central
- ISSN：1465-6906
文摘
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.