Brd4‐Brd2 isoform switching coordinates pluripotent exit and Smad2‐dependent lineage specification

Fernandez-Alonso, Rosalia; Davidson, L. S. P.; Hukelmann, Jens; Zengerle, Michael; Prescott, Alan R.; Lamond, Angus I.; Ciulli, A.; Sapkota, Gopal P.; Findlay, Greg M.

doi:10.15252/embr.201643534

Cited by 22 publications

(18 citation statements)

References 49 publications

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“…Since ZNF281 is involved in inducing epithelial–mesenchymal transition (EMT) and promotes metastatis [52], anti-oncogenic effects of JQ1 on H23 cells may partly be due to downregulation of ZNF281, presumably through dissociation of BRD2, which may lead to disrupted EMT in lung cancer. Interestingly, a recent study showed that BRD2 activates expression of genes involved in EMT induction, whereas BRD3 and BRD4 exert opposite functions [53], supporting distinct roles of BRD2 among the somatic BET proteins [34,35,54,55]. Other TFs identified by MARA but not discussed here may be involved in the BRD2-associated transcriptional regulation.…”

Section: Discussionmentioning

confidence: 53%

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko¹,

Kaczkowski²,

Hon³

et al. 2018

Epigenetics

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The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found that a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and -independent manner.

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Section: Discussionmentioning

confidence: 53%

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko¹,

Kaczkowski²,

Hon³

et al. 2018

Epigenetics

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“…Mice with homozygous disruption of either Brd2 or Brd4 die during embryogenesis [51,52]. BRD4 is required for maintaining the self-renewal and pluripotency of stem cells [53,54] and BRD2 for lineage specification [55]. Inducible knockdown of BRD4 by RNAi interferes with normal hematopoiesis and leads to epidermal hyperplasia and stem cell depletion [35].…”

Section: Discussionmentioning

confidence: 99%

Bromodomain and extra-terminal domain (BET) proteins regulate melanocyte differentiation

Trivedi

Mehrotra

Baum

et al. 2020

Epigenetics & Chromatin

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Background: Pharmacologic inhibition of bromodomain and extra-terminal (BET) proteins is currently being explored as a new therapeutic approach in cancer. Some studies have also implicated BET proteins as regulators of cell identity and differentiation through their interactions with lineage-specific factors. However, the role of BET proteins has not yet been investigated in melanocyte differentiation. Melanocyte inducing transcription factor (MITF) is the master regulator of melanocyte differentiation, essential for pigmentation and melanocyte survival. In this study, we tested the hypothesis that BET proteins regulate melanocyte differentiation through interactions with MITF. Results: Here we show that chemical inhibition of BET proteins prevents differentiation of unpigmented melanoblasts into pigmented melanocytes and results in de-pigmentation of differentiated melanocytes. BET inhibition also slowed cell growth, without causing cell death, increasing the number of cells in G1. Transcriptional profiling revealed that BET inhibition resulted in decreased expression of pigment-specific genes, including many MITF targets. The expression of pigment-specific genes was also down-regulated in melanoma cells, but to a lesser extent. We found that RNAi depletion of the BET family members, bromodomain-containing protein 4 (BRD4) and bromodomaincontaining protein 2 (BRD2) inhibited expression of two melanin synthesis enzymes, TYR and TYRP1. Both BRD4 and BRD2 were detected on melanocyte promoters surrounding MITF-binding sites, were associated with open chromatin structure, and promoted MITF binding to these sites. Furthermore, BRD4 and BRD2 physically interacted with MITF. Conclusion: These findings indicate a requirement for BET proteins in the regulation of pigmentation and melanocyte differentiation. We identified changes in pigmentation specific gene expression that occur upon BET inhibition in melanoblasts, melanocytes, and melanoma cells.

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“…Quantitative total cell proteomics. Quantitative total cell proteomics analysis was conducted as described 19 . mESCs were cultured in LIF/FBS, lysed, boiled and sonicated before alkylation with iodoacetamide.…”

Section: Methodsmentioning

confidence: 99%

Phosphoproteomics identifies a bimodal EPHA2 receptor switch that promotes embryonic stem cell differentiation

et al. 2020

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Embryonic Stem Cell (ESC) differentiation requires complex cell signalling network dynamics, although the key molecular events remain poorly understood. Here, we use phosphoproteomics to identify an FGF4-mediated phosphorylation switch centred upon the key Ephrin receptor EPHA2 in differentiating ESCs. We show that EPHA2 maintains pluripotency and restrains commitment by antagonising ERK1/2 signalling. Upon ESC differentiation, FGF4 utilises a bimodal strategy to disable EPHA2, which is accompanied by transcriptional induction of EFN ligands. Mechanistically, FGF4-ERK1/2-RSK signalling inhibits EPHA2 via Ser/Thr phosphorylation, whilst FGF4-ERK1/2 disrupts a core pluripotency transcriptional circuit required for Epha2 gene expression. This system also operates in mouse and human embryos, where EPHA receptors are enriched in pluripotent cells whilst surrounding lineagespecified trophectoderm expresses EFNA ligands. Our data provide insight into function and regulation of EPH-EFN signalling in ESCs, and suggest that segregated EPH-EFN expression coordinates cell fate with compartmentalisation during early embryonic development.

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Brd4‐Brd2 isoform switching coordinates pluripotent exit and Smad2‐dependent lineage specification

Cited by 22 publications

References 49 publications

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Bromodomain and extra-terminal domain (BET) proteins regulate melanocyte differentiation

Phosphoproteomics identifies a bimodal EPHA2 receptor switch that promotes embryonic stem cell differentiation

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