Nonlinear relationship between chromatin accessibility and estradiol-regulated gene expression.
Oncogene
; 40(7): 1332-1346, 2021 02.
Article
em En
| MEDLINE
| ID: mdl-33420376
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.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
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Outros_tipos
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
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Receptor alfa de Estrogênio
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Estradiol
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Fator de Transcrição GATA3
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Fator 3-alfa Nuclear de Hepatócito
Limite:
Female
/
Humans
Idioma:
En
Revista:
Oncogene
Assunto da revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos