Chen, DuojiaoParker, Taylor M.Bhat-Nakshatri, PoornimaChu, XiaonaLiu, YunlongWang, YueNakshatri, Harikrishna2023-06-162023-06-162021-02Chen, D., Parker, T. M., Bhat-Nakshatri, P., Chu, X., Liu, Y., Wang, Y., & Nakshatri, H. (2021). Nonlinear relationship between chromatin accessibility and estradiol-regulated gene expression. Oncogene, 40(7), Article 7. https://doi.org/10.1038/s41388-020-01607-20950-9232, 1476-5594https://hdl.handle.net/1805/33841Chromatin accessibility is central to basal and inducible gene expression. Through ATAC-seq experiments in estrogen receptor-positive (ER+) breast cancer cell line MCF-7 and integration with multi-omics data, we found estradiol (E2) induced chromatin accessibility changes in a small number of breast cancer-relevant E2-regulated genes. As expected, open chromatin regions associated with E2-inducible gene expression showed enrichment of estrogen response element (ERE) and those associated with E2-repressible gene expression were enriched for ERE, PBX1, and PBX3. While a significant number of open chromatin regions showed pioneer factor FOXA1 occupancy in the absence of E2, E2-treatment further enhanced FOXA1 occupancy suggesting that ER–E2 enhances chromatin occupancy of FOXA1 to a subset of E2-regulated genes. Surprisingly, promoters of 80% and enhancers of 60% of E2-inducible genes displayed closed chromatin configuration both in the absence and presence of E2. Integration of ATAC-seq data with ERα ChIP-seq data revealed that ~40% ERα binding sites in the genome are found in chromatin regions that are not accessible as per ATAC-seq. Such ERα binding regions were enriched for binding sites of multiple nuclear receptors including ER, ESRRB, ERRγ, COUP-TFII (NR2F2), RARα, EAR2 as well as traditional pioneer factors FOXA1 and GATA3. Similar data were also obtained when ERα ChIP-seq data were integrated with MNase-seq and DNase-seq data sets. In summation, our results reveal complex mechanisms of ER–E2 interaction with nucleosomes. Notably, “closed chromatin” configuration as defined by ATAC-seq or by other techniques is not necessarily associated with lack of gene expression and technical limitations may preclude ATAC-seq to demonstrate accessibility of chromatin regions that are bound by ERα.en-USPublisher PolicyBreast cancerChromatinestrogen receptor-positiveArticle