Article ; Online: Nonlinear relationship between chromatin accessibility and estradiol-regulated gene expression.
2021 Volume 40, Issue 7, Page(s) 1332–1346
Abstract: Chromatin 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 ... ...
| Abstract | Chromatin 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. |
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| MeSH term(s) | Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; COUP Transcription Factor II/genetics ; Cell Line, Tumor ; Chromatin/genetics ; Estradiol/genetics ; Estradiol/metabolism ; Estrogen Receptor alpha/genetics ; Female ; GATA3 Transcription Factor/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Hepatocyte Nuclear Factor 3-alpha/genetics ; Humans ; MCF-7 Cells ; Promoter Regions, Genetic/genetics ; Receptors, Estrogen/genetics ; Retinoic Acid Receptor alpha/genetics |
| Chemical Substances | COUP Transcription Factor II ; Chromatin ; ESRRB protein, human ; Estrogen Receptor alpha ; FOXA1 protein, human ; GATA3 Transcription Factor ; GATA3 protein, human ; Hepatocyte Nuclear Factor 3-alpha ; NR2F2 protein, human ; Receptors, Estrogen ; Retinoic Acid Receptor alpha ; Estradiol (4TI98Z838E) |
| Language | English |
| Publishing date | 2021-01-08 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 639046-8 |
| ISSN | 1476-5594 ; 0950-9232 |
| ISSN (online) | 1476-5594 |
| ISSN | 0950-9232 |
| DOI | 10.1038/s41388-020-01607-2 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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