Chromosome-specific retention of cancer-associated DNA hypermethylation following pharmacological inhibition of DNMT1

• Published in: Communications biology Vol. 5; no. 1; pp. 528 - 10
• Main Authors: Wiseman, Ashley K., Tiedemann, Rochelle L., Fan, Huihui, Shen, Hui, Madaj, Zachary, McCabe, Michael T., Pappalardi, Melissa B., Jones, Peter A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.06.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 38; 38/22; 38/39; 38/61; 38/77; 38/90; 45; 631/208/176/1988; 631/67/68/2486; Biology; Biomedical and Life Sciences; Cancer; Colon cancer; Colorectal carcinoma; Computer applications; CpG islands; DNA fingerprinting; DNA methylation; DNA methyltransferase; DNMT1 protein; Epigenetics; Life Sciences; Retention; Tumor cell lines; Tumors; X chromosomes
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03509-3

The DNA methylation status of the X-chromosome in cancer cells is often overlooked because of computational difficulties. Most of the CpG islands on the X-chromosome are mono-allelically methylated in normal female cells and only present as a single copy in male cells. We treated two colorectal cancer cell lines from a male (HCT116) and a female (RKO) with increasing doses of a DNA methyltransferase 1 (DNMT1)-specific inhibitor (GSK3685032/GSK5032) over several months to remove as much non-essential CpG methylation as possible. Profiling of the remaining DNA methylome revealed an unexpected, enriched retention of DNA methylation on the X-chromosome. Strikingly, the identified retained X-chromosome DNA methylation patterns accurately predicted de novo DNA hypermethylation in colon cancer patient methylomes in the TCGA COAD/READ cohort. These results suggest that a re-examination of tumors for X-linked DNA methylation changes may enable greater understanding of the importance of epigenetic silencing of cancer related genes. Chromosome specific retention of cancer associated DNA hypermethylation following pharmacological inhibition of DNMT1 is shown, with residual CpG methylation on the X chromosome compared to autosomes, suggesting a separate mechanism of methylation.