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Regulation of DNA Methylation at Enhancers by TET2 Finetunes Gene Transcription in ERα-Positive Breast Cancer Cells

ABSTRACT: Background: Aberrant DNA methylation is an epigenetic hallmark of most malignant tumors including breast cancer. However, the exact role of TET2-mediated DNA demethylation in ERα-positive luminal breast cancer is not well understood. Results: Here we showed by TCGA analyses that lower TET2 mRNA expression level is associated with worse clinical outcomes (i.e., overall survival) in ERα-positive but not ERα-negative breast cancer. Moreover, depletion of TET2 by CRISPR/Cas9 results in increased tumorigenesis capability of MCF7 cells in vitro. Whole genome bisulfite sequencing (WGBS) analysis revealed that DNA hypermethylation (gain-of-5mC) occurs within a subgroup of enhancers including estrogen responsive element (EREs) in MCF7 cells upon TET2 depletion. ChIP-seq and RNA-seq analysis showed that TET2 depletion impairs E2-induced ERα binding to these ‘gain-of-5mC’ EREs and gene transcription. Conclusions: Our data suggest that TET2-mediated enhancer DNA demethylation fine-tunes ERα-dependent and independent gene transcription in ERα-positive breast cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE136673 | GEO | 2020/07/09

REPOSITORIES: GEO

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