De novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG islands

Roza H. Ali Masalmeh, Francesca Taglini, Cristina Rubio-Ramon, Kamila I. Musialik, Jonathan Higham, Hazel Davidson-Smith, Ioannis Kafetzopoulos, Kamila P. Pawlicka, Hannah M. Finan, Richard Clark, Jimi Wills, Andrew J. Finch, Lee Murphy and Duncan Sproul ()
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Roza H. Ali Masalmeh: University of Edinburgh
Francesca Taglini: University of Edinburgh
Cristina Rubio-Ramon: University of Edinburgh
Kamila I. Musialik: University of Edinburgh
Jonathan Higham: University of Edinburgh
Hazel Davidson-Smith: University of Edinburgh
Ioannis Kafetzopoulos: University of Edinburgh
Kamila P. Pawlicka: University of Edinburgh
Hannah M. Finan: University of Edinburgh
Richard Clark: University of Edinburgh
Jimi Wills: University of Edinburgh
Andrew J. Finch: University of Edinburgh
Lee Murphy: University of Edinburgh
Duncan Sproul: University of Edinburgh

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract The aberrant gain of DNA methylation at CpG islands is frequently observed in colorectal tumours and may silence the expression of tumour suppressors such as MLH1. Current models propose that these CpG islands are targeted by de novo DNA methyltransferases in a sequence-specific manner, but this has not been tested. Using ectopically integrated CpG islands, here we find that aberrantly methylated CpG islands are subject to low levels of de novo DNA methylation activity in colorectal cancer cells. By delineating DNA methyltransferase targets, we find that instead de novo DNA methylation activity is targeted primarily to CpG islands marked by the histone modification H3K36me3, a mark associated with transcriptional elongation. These H3K36me3 marked CpG islands are heavily methylated in colorectal tumours and the normal colon suggesting that de novo DNA methyltransferase activity at CpG islands in colorectal cancer is focused on similar targets to normal tissues and not greatly remodelled by tumourigenesis.

Date: 2021
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DOI: 10.1038/s41467-020-20716-w

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