Sankari Nagarajan, Upasana Bedi, Anusha Budida, Feda H. Hamdan, Vivek Kumar Mishra, Zeynab Najafova, Wanhua Xie, Malik Alawi, Daniela Indenbirken, Stefan Knapp, Cheng-Ming Chiang, Adam Grundhoff, Vijayalakshmi Kari, Christina H. Scheel, Florian Wegwitz, Steven A. Johnsen
- Bromodomain-containing protein 4 (BRD4) is a member of the bromo- and extraterminal (BET) domain-containing family of epigenetic readers which is under intensive investigation as a target for anti-tumor therapy. BRD4 plays a central role in promoting the expression of select subsets of genes including many driven by oncogenic transcription factors and signaling pathways. However, the role of BRD4 and the effects of BET inhibitors in non-transformed cells remain mostly unclear. We demonstrate that BRD4 is required for the maintenance of a basal epithelial phenotype by regulating the expression of epithelial-specific genes including TP63 and Grainy Head-like transcription factor-3 (GRHL3) in non-transformed basal-like mammary epithelial cells. Moreover, BRD4 occupancy correlates with enhancer activity and enhancer RNA (eRNA) transcription. Motif analyses of cell context-specific BRD4-enriched regions predicted the involvement of FOXO transcription factors. Consistently, activation of FOXO1 function via inhibition of EGFR-AKT signaling promoted the expression of TP63 and GRHL3. Moreover, activation of Src kinase signaling and FOXO1 inhibition decreased the expression of FOXO/BRD4 target genes. Together, our findings support a function for BRD4 in promoting basal mammary cell epithelial differentiation, at least in part, by regulating FOXO factor function on enhancers to activate TP63 and GRHL3 expression.
MetadatenAuthor: | Sankari Nagarajan, Upasana Bedi, Anusha Budida, Feda H. Hamdan, Vivek Kumar Mishra, Zeynab Najafova, Wanhua Xie, Malik Alawi, Daniela Indenbirken, Stefan KnappORCiDGND, Cheng-Ming Chiang, Adam Grundhoff, Vijayalakshmi Kari, Christina H. Scheel, Florian Wegwitz, Steven A. Johnsen |
---|
URN: | urn:nbn:de:hebis:30:3-439384 |
---|
DOI: | https://doi.org/10.1093/nar/gkw1276 |
---|
ISSN: | 1362-4962 |
---|
ISSN: | 0305-1048 |
---|
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/27980063 |
---|
Parent Title (English): | Nucleic acids research |
---|
Publisher: | Oxford Univ. Press |
---|
Place of publication: | Oxford |
---|
Document Type: | Article |
---|
Language: | English |
---|
Date of Publication (online): | 2017/08/24 |
---|
Year of first Publication: | 2016 |
---|
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
---|
Release Date: | 2017/08/24 |
---|
Tag: | enhancer of transcription; epigenetics; epithelial cells; epithelium; forkhead box protein o1; genes; phenotype; proto-oncogene proteins c-akt; rna; signal transduction; tp63 gene; transcription factor |
---|
Volume: | 45 |
---|
Issue: | 6 |
---|
Page Number: | 16 |
---|
First Page: | 3130 |
---|
Last Page: | 3145 |
---|
Note: | The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
---|
HeBIS-PPN: | 425145166 |
---|
Institutes: | Biochemie, Chemie und Pharmazie / Pharmazie |
---|
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
---|
Sammlungen: | Universitätspublikationen |
---|
Licence (English): | Creative Commons - Namensnennung-Nicht kommerziell 4.0 |
---|