BRD4 localization to lineage-specific enhancers is associated with a distinct transcription factor repertoire

Najafova, Zeynab; Tirado-Magallanes, Roberto; Subramaniam, Malayannan; Hossan, Tareq; Schmídt, G.; Nagarajan, Sankari; Baumgart, Simon J.; Mishra, Vivek Kumar; Bedi, Upasana; Hesse, Eric; Knapp, S.; Hawse, John R.; Johnsen, Steven A.

doi:10.1093/nar/gkw826

Cited by 92 publications

(129 citation statements)

References 84 publications

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“…These findings support previous studies which demonstrate that early tissue‐specific loss of Brd4 prevents lineage commitment of myoblasts and adipocytes (J. E. Lee et al, ). Additionally, Brd4 inhibition has been shown to prevent differentiation of human fetal osteoblasts (Najafova et al, ) and slow progression of osteosarcoma cells (Lamoureux et al, ). Our findings corroborate these previous observations in MC3T3 osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

“…This family of epigenetic reader proteins provides a plausible link between histone modifications and subsequent activation of the osteoblastic transcriptional network. Indeed, prior studies have suggested that Brd4 may contribute to biological regulation of osteogenesis (Baud'huin et al, ; Najafova et al, ). In the current study, we evaluated the expression levels of a large panel of BRD proteins ( n = 40), including multiple BET proteins ( n = 7) in MC3T3 osteoblasts and assessed the impact of Brd2 and Brd4 loss of function by small interfering RNA (siRNA)‐mediated knock‐down and small molecule inhibition.…”

Section: Introductionmentioning

confidence: 99%

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The epigenetic reader Brd4 is required for osteoblast differentiation

Paradise

Galvan

Kubrova

et al. 2019

Journal Cellular Physiology

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Transcription networks and epigenetic mechanisms including DNA methylation, histone modifications, and noncoding RNAs control lineage commitment of multipotent mesenchymal progenitor cells. Proteins that read, write, and erase histone tail modifications curate and interpret the highly intricate histone code. Epigenetic reader proteins that recognize and bind histone marks provide a crucial link between histone modifications and their downstream biological effects. Here, we investigate the role of bromodomain‐containing (BRD) proteins, which recognize acetylated histones, during osteogenic differentiation. Using RNA‐sequencing (RNA‐seq) analysis, we screened for BRD proteins (n = 40) that are robustly expressed in MC3T3 osteoblasts. We focused functional follow‐up studies on Brd2 and Brd4 which are highly expressed in MC3T3 preosteoblasts and represent “bromodomain and extra terminal domain” (BET) proteins that are sensitive to pharmacological agents (BET inhibitors). We show that small interfering RNA depletion of Brd4 has stronger inhibitory effects on osteoblast differentiation than Brd2 loss as measured by osteoblast‐related gene expression, extracellular matrix deposition, and alkaline phosphatase activity. Similar effects on osteoblast differentiation are seen with the BET inhibitor +JQ1, and this effect is reversible upon its removal indicating that this small molecule has no lasting effects on the differentiation capacity of MC3T3 cells. Mechanistically, we find that Brd4 binds at known Runx2 binding sites in promoters of bone‐related genes. Collectively, these findings suggest that Brd4 is recruited to osteoblast‐specific genes and may cooperate with bone‐related transcription factors to promote osteoblast lineage commitment and maturation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The epigenetic reader Brd4 is required for osteoblast differentiation

Paradise

Galvan

Kubrova

et al. 2019

Journal Cellular Physiology

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“…Various studies highlight the central role of BRD4 in enhancer activity (6–9,26). This study reveals a specific association of BRD4 with distal regions of basal epithelial-specific genes.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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“…BRD4 is a central regulator of lineage- and tumor-specific transcriptional progams and functions to increase transcriptional activity by binding to acetylated lysine residues at distal and proximal regulatory regions (30,34,35). CHD1-dependent genes showed a high occupancy of CHD1 which extended into the gene body, while displaying comparatively low RNAPII occupancy around the TSS (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

CHD1 regulates cell fate determination by activation of differentiation-induced genes

Baumgart

Najafova

Hossan

et al. 2017

Nucleic Acids Research

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The coordinated temporal and spatial activation of gene expression is essential for proper stem cell differentiation. The Chromodomain Helicase DNA-binding protein 1 (CHD1) is a chromatin remodeler closely associated with transcription and nucleosome turnover downstream of the transcriptional start site (TSS). In this study, we show that CHD1 is required for the induction of osteoblast-specific gene expression, extracellular-matrix mineralization and ectopic bone formation in vivo. Genome-wide occupancy analyses revealed increased CHD1 occupancy around the TSS of differentiation-activated genes. Furthermore, we observed that CHD1-dependent genes are mainly induced during osteoblast differentiation and are characterized by higher levels of CHD1 occupancy around the TSS. Interestingly, CHD1 depletion resulted in increased pausing of RNA Polymerase II (RNAPII) and decreased H2A.Z occupancy close to the TSS, but not at enhancer regions. These findings reveal a novel role for CHD1 during osteoblast differentiation and provide further insights into the intricacies of epigenetic regulatory mechanisms controlling cell fate determination.

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BRD4 localization to lineage-specific enhancers is associated with a distinct transcription factor repertoire

Cited by 92 publications

References 84 publications

The epigenetic reader Brd4 is required for osteoblast differentiation

The epigenetic reader Brd4 is required for osteoblast differentiation

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

CHD1 regulates cell fate determination by activation of differentiation-induced genes

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