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

• Published in: Nature communications Vol. 12; no. 1; pp. 694 - 13
• Main Authors: Masalmeh, Roza H. Ali, Taglini, Francesca, Rubio-Ramon, Cristina, Musialik, Kamila I., Higham, Jonathan, Davidson-Smith, Hazel, Kafetzopoulos, Ioannis, Pawlicka, Kamila P., Finan, Hannah M., Clark, Richard, Wills, Jimi, Finch, Andrew J., Murphy, Lee, Sproul, Duncan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 38/1; 38/109; 38/15; 38/22; 38/77; 631/208/176; 631/208/177; 631/337/176/1988; 631/67/68/2486; 692/4028/67/1504/1885; Aberration; Cancer; Carcinogenesis - genetics; Cell Line, Tumor; Chromatin Immunoprecipitation Sequencing; Colon; Colon - pathology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; CpG islands; CpG Islands - genetics; Datasets as Topic; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation; DNA methyltransferase; Elongation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Histone Code - genetics; Histones; Histones - genetics; Humanities and Social Sciences; Humans; Islands; MLH1 protein; multidisciplinary; Nucleotide sequence; Promoter Regions, Genetic - genetics; Science; Science (multidisciplinary); Suppressors; Transcription elongation; Transcription, Genetic; Tumorigenesis; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20716-w

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. Aberrant gain of DNA methylation at CpG islands is frequently observed in colorectal tumours. Here the authors use ectopically integrated CpG islands in colorectal cancer cells and find that aberrantly methylated CpG islands are subject to low levels of de novo DNA methylation, and that instead de novo DNA methylation activity is targeted primarily to CpG islands marked by the histone modification H3K36me3.