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

ABSTRACT: 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 novel DNA methyltransferase 1 (DNMT1)-specific inhibitor (GSK3685032/GSK5032) over a long time period to remove as much non-essential CpG methylation as possible. Analysis of the residual methylation patterns in the heavily treated cells showed a very surprising non-uniform distribution of retained methylation on specific chromosomes. For example, probes on the X-chromosome preferentially retained methylation 2-3-fold more frequently compared to those on autosomes. This was true for probes methylated on the active X chromosome in normal cells such as XIST and also for genes which acquired methylation in cancer such as ARMCX2 and MAGEH1. The maintenance of high DNA methylation on a subset of probes after such exhaustive treatment suggests that it might have functional significance for cell survival. Importantly, the same X-linked probes we found in the treated cells were also methylated in a large number of colorectal/rectal cancers in the TCGA data set and to a lesser extent in other cancer types. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182209 | GEO | 2022/06/23

REPOSITORIES: GEO

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