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

Zhang Yusheng, Chan Ho Lam, Garcia-Martinez Liliana, Karl Daniel L., Weich Natalia, Slingerland Joyce M., Verdun Ramiro E., Morey Lluis

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  (ER). Whether ER-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 ER, FOXA1, and GRHL2 cobound sites and regulates estrogen-induced enhancers and ER recruitment. Last, ChIP exo revealed multiple binding events of these factors at single-nucleotide resolution, including RING1B occupancy approximately 10 base pairs around ER bound sites. We propose RING1B as a key regulator of the dynamic, liganded-ER transcriptional regulatory circuit in luminal BC.


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June, 2020


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