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BAP18 facilitates CTCF-mediated chromatin accessible to regulate enhancer activity in breast cancer

Sun Ge,Wei Yuntao,Zhou Baosheng,Wang Manlin,Luan Ruina,Bai Yu,Li Hao,Wang Shan,Zheng Dantong,Wang Chunyu,Wang Shengli,Zeng Kai,Liu Shuchang,Lin Lin,He Mingcong,Zhang Qiang,Zhao Yue

The estrogen receptor alpha (ERα) signaling pathway is a crucial target for ERα-positive breast cancer therapeutic strategies. Co-regulators and other transcription factors cooperate for effective ERα-related enhancer activation. Recent studies demonstrate that the transcription factor CTCF is essential to participate in ERα/E2-induced enhancer transactivation. However, the mechanism of how CTCF is achieved remains unknown. Here, we provided evidence that BAP18 is required for CTCF recruitment on ERα-enriched enhancers, facilitating CTCF-mediated chromatin accessibility to promote enhancer RNAs transcription. Consistently, GRO-seq demonstrates that the enhancer activity is positively correlated with BAP18 enrichment. Furthermore, BAP18 interacts with SMARCA1/BPTF to accelerate the recruitment of CTCF to ERα-related enhancers. Interestingly, BAP18 is involved in chromatin accessibility within enhancer regions, thereby increasing enhancer transactivation and enhancer-promoter looping. BAP18 depletion increases the sensitivity of anti-estrogen and anti-enhancer treatment in MCF7 cells. Collectively, our study indicates that BAP18 coordinates with CTCF to enlarge the transactivation of ERα-related enhancers, providing a better understanding of BAP18/CTCF coupling chromatin remodeling and E-P looping in the regulation of enhancer transcription.