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.
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The data and material that support the findings of this study are available from the corresponding author upon reasonable request.
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We thank Professor Kato Shigeaki from center of regional cooperation in Iwaki Meisei University for his important discussion and support. We appreciate Dr. Yunlong Huo and Dr. Fang Dong for their excellent technical assistance. We thank SeqHealth Tech Co., Ltd Wuhan, China, for ChIP-seq and ATAC-seq analysis.
This study was supported by the National Natural Science Foundation of China (32170603, 31871286 for YZ, 81872015, 82273123 for CW, 32100440 for GS); China Postdoctoral Science Foundation (276066) for GS; Foundation of Liaoning Province of China (LJKZ0756 for Shengli Wang); Local projects supported by the central government (2022JH6/100100035 for YZ); Foreign expert project of Ministry of Science and Technology (G2022006007L for YZ).
The authors declare no competing interests.
Our study makes use of publicly available sequencing datasets as cited in the results section. As such, prior ethics approval has been obtained for these studies and no additional approval is required. All primary breast cancer tissues and adjacent tissues of patients were procured from the Liaoning Cancer Hospital of China Medical University, all of which received permission from patients already.
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Sun, G., Wei, Y., Zhou, B. et al. BAP18 facilitates CTCF-mediated chromatin accessible to regulate enhancer activity in breast cancer. Cell Death Differ 30, 1260–1278 (2023). https://doi.org/10.1038/s41418-023-01135-y