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  • Estrogen induces dynamic ERα and RING1B recruitment to control gene and enhancer activities in luminal breast cancer.

Estrogen induces dynamic ERα and RING1B recruitment to control gene and enhancer activities in luminal breast cancer.

Science advances (2020-06-18)
Yusheng Zhang, Ho Lam Chan, Liliana Garcia-Martinez, Daniel L Karl, Natalia Weich, Joyce M Slingerland, Ramiro E Verdun, Lluis Morey
ABSTRACT

RING1B, a core Polycomb repressive complex 1 subunit, is a histone H2A ubiquitin ligase essential for development. RING1B is overexpressed in patients with luminal breast cancer (BC) and recruited to actively transcribed genes and enhancers co-occupied by the estrogen receptor α (ERα). Whether ERα-induced transcriptional programs are mediated by RING1B is not understood. We show that prolonged estrogen administration induces transcriptional output and chromatin landscape fluctuations. RING1B loss impairs full estrogen-mediated gene expression and chromatin accessibility for key BC transcription factors. These effects were mediated, in part, by RING1B enzymatic activity and nucleosome binding functions. RING1B is recruited in a cyclic manner to ERα, FOXA1, and GRHL2 cobound sites and regulates estrogen-induced enhancers and ERα recruitment. Last, ChIP exo revealed multiple binding events of these factors at single-nucleotide resolution, including RING1B occupancy approximately 10 base pairs around ERα bound sites. We propose RING1B as a key regulator of the dynamic, liganded-ERα transcriptional regulatory circuit in luminal BC.

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