Transcriptomics

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Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated CRC. [RNA-Seq]


ABSTRACT: BRAFV600E-mutated colorectal cancer (CRC) exhibits a strong correlation with DNA hypermethylation suggesting this subgroup of tumors is uniquely presenting epigenomic phenotypes. Nonetheless, the traditional epigenomic therapeutic agent, 5-azacitidine, which inhibits DNA methyltransferase activity, did not yield sufficient improvements in the efficacies of BRAFV600E CRC in vivo. We utilized a patient-derived xenograft model and confirmed an effective reduction of DNA methylation levels upon 5-azacitidine treatment yet failed to restore gene expression patterns. This study unbiasedly explored the adaptive engagement of other epigenomic modifications upon the profound decrease in DNA methylation by azacitidine treatment. A loss of histone acetylation and a gain of histone methylations, including H3K27 and H3K4 trimethylation, were observed around hypomethylated regions. Our findings suggested a compensatory increase in repressive histone mark, H3K27 trimethylation, around treatment-induced hypomethylated regions, which suggests the involvement of polycomb repressive complex (PRC) activity around the genome with lost DNA methylation, therefore maintaining the suppression of key genes. Combined inhibition of PRC activity through EZH2 inhibitor with azacitidine treatment additively improved efficacies in BRAFV600E CRC cells. In conclusion, DNA hypermethylation exhibits a close association with H3K27me3 and PRC activity in BRAFV600E CRC, and simultaneous blockade of DNMT and EZH2 holds promise as a potential therapeutic strategy for patients with BRAFV600E-mutated CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254279 | GEO | 2024/09/01

REPOSITORIES: GEO

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