BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells

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

Research output: Contribution to journalArticle

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Abstract

Bromodomain-containing protein 4 (BRD4) is amember of the bromo-and extraterminal (BET) domaincontaining 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 epithelialspecific 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 FOXOtranscription 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.

Original languageEnglish (US)
Pages (from-to)3130-3145
Number of pages16
JournalNucleic Acids Research
Volume45
Issue number6
DOIs
StatePublished - 2016

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Transcription Factor 3
Breast
Epithelial Cells
Head
Proteins
src-Family Kinases
Epigenomics
Genes
Cell Differentiation
Transcription Factors
Maintenance
RNA
Phenotype
Gene Expression

ASJC Scopus subject areas

  • Genetics

Cite this

Nagarajan, S., Bedi, U., Budida, A., Hamdan, F. H., Mishra, V. K., Najafova, Z., ... Johnsen, S. A. (2016). BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells. Nucleic Acids Research, 45(6), 3130-3145. https://doi.org/10.1093/nar/gkw1276

BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells. / Nagarajan, Sankari; Bedi, Upasana; Budida, Anusha; Hamdan, Feda H.; Mishra, Vivek Kumar; Najafova, Zeynab; Xie, Wanhua; Alawi, Malik; Indenbirken, Daniela; Knapp, Stefan; Chiang, Cheng Ming; Grundhoff, Adam; Kari, Vijayalakshmi; Scheel, Christina H.; Wegwitz, Florian; Johnsen, Steven A.

In: Nucleic Acids Research, Vol. 45, No. 6, 2016, p. 3130-3145.

Research output: Contribution to journalArticle

Nagarajan, S, Bedi, U, Budida, A, Hamdan, FH, Mishra, VK, Najafova, Z, Xie, W, Alawi, M, Indenbirken, D, Knapp, S, Chiang, CM, Grundhoff, A, Kari, V, Scheel, CH, Wegwitz, F & Johnsen, SA 2016, 'BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells', Nucleic Acids Research, vol. 45, no. 6, pp. 3130-3145. https://doi.org/10.1093/nar/gkw1276
Nagarajan S, Bedi U, Budida A, Hamdan FH, Mishra VK, Najafova Z et al. BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells. Nucleic Acids Research. 2016;45(6):3130-3145. https://doi.org/10.1093/nar/gkw1276
Nagarajan, Sankari ; Bedi, Upasana ; Budida, Anusha ; Hamdan, Feda H. ; Mishra, Vivek Kumar ; Najafova, Zeynab ; Xie, Wanhua ; Alawi, Malik ; Indenbirken, Daniela ; Knapp, Stefan ; Chiang, Cheng Ming ; Grundhoff, Adam ; Kari, Vijayalakshmi ; Scheel, Christina H. ; Wegwitz, Florian ; Johnsen, Steven A. / BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells. In: Nucleic Acids Research. 2016 ; Vol. 45, No. 6. pp. 3130-3145.
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AU - Bedi, Upasana

AU - Budida, Anusha

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AU - Mishra, Vivek Kumar

AU - Najafova, Zeynab

AU - Xie, Wanhua

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AU - Knapp, Stefan

AU - Chiang, Cheng Ming

AU - Grundhoff, Adam

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AU - Wegwitz, Florian

AU - Johnsen, Steven A.

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