Tumour suppressor TET2 safeguards enhancers from aberrant DNA methylation and epigenetic reprogramming in ERα-positive breast cancer cells

ABSTRACT

Aberrant DNA methylation is an epigenetic hallmark of malignant tumours. The DNA methylation level is regulated by not only DNA methyltransferases (DNMTs) but also Ten-Eleven Translocation (TET) family proteins. However, the exact role of TET genes in breast cancer remains controversial. Here, we uncover that the ERα-positive breast cancer patients with high TET2 mRNA expression had better overall survival rates. Consistently, knockout of TET2 promotes the tumorigenesis of ERα-positive MCF7 breast cancer cells. Mechanistically, TET2 loss leads to aberrant DNA methylation (gain of 5mC) at a large proportion of enhancers, accompanied by significant reduction in H3K4me1 and H3K27ac enrichment. By analysing the epigenetically reprogrammed enhancers, we identify oestrogen responsive element (ERE) as one of the enriched motifs of transcriptional factors. Importantly, TET2 loss impairs 17beta-oestradiol (E2)-induced transcription of the epigenetically reprogrammed EREs-associated genes through attenuating the binding of ERα. Taken together, these findings shed light on our understanding of the epigenetic mechanisms underlying the enhancer reprogramming during breast cancer pathogenesis.

KEYWORDS:

• Breast cancer
• TET2
• enhancer
• ERα

Acknowledgments

We thank Dr. Zhennan Shi for constructing the TET2 KO MCF-7 cells and Dr. Lei Zhang for performing HPLC/MS analysis.

Disclosure statement

The authors declare that they have no competing interests.

Author contributions

LT and RL conceived the project. RL performed the bioinformatic analysis. XZ, YS, and LX performed the experiments. LL and CA provided assistance in performing the experiments. HL and FW provided assistance in the bioinformatic analysis. LT, RL, XZ wrote the manuscript with the Input from all authors. All authors read and approved the final manuscript.

Data availability

The ERα ChIP-seq data in MCF7 cells were collected from the GEO database under accession number GSM1469980. ChIP-seq data of H3K4me1 and H3K27ac for MCF7 cells were collected from the GEO database under accession number GSM2308527 and GSM945854.

Our own raw and processed nucleic acid sequencing data (WGBS, H3K4me1 and H3K27ac ChIP-seq, RNA-seq, and ERα ChIP-seq) for WT and TET2 KO MCF7 cells have been deposited in NCBI Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE136673.

Most analyses were performed using publicly available software, and the codes used for statistical analysis are available upon request.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (81672785, 31871291, and 82073113) and the National Key R&D Project of China (2016YFA0101800). LT was also supported by the innovative research team of high-level local university in Shanghai.