Transcription Factor AP1 Potentiates Chromatin Accessibility and Glucocorticoid Receptor Binding

Biddie, Simon C.; John, Sam; Sabo, Pete J.; Thurman, Robert E.; Johnson, Thomas A.; Schiltz, R. Louis; Miranda, Tina Branscombe; Sung, Myong-Hee; Trump, Saskia; Lightman, Stafford L.; Vinson, Charles; Stamatoyannopoulos, J; Hager, Gordon L.

doi:10.1016/j.molcel.2011.06.016

Cited by 415 publications

(404 citation statements)

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“…Another interesting finding is that the identity of the leading factor at facilitated binding sites appears to be determined by motif strength; i.e., at sites where C/EBP␣ is the leading factor, the C/EBP␣ motif is generally strong and the PPAR␥ motif is weak and vice versa. This is in line with the finding that GR has pioneering potential at a subset of GR binding sites with a high incidence of the GR binding motif (61).…”

Section: Discussionsupporting

confidence: 89%

“…More recent genome-wide profiling of transcription factor binding combined with loss-of-function analyses has revealed that some transcription factors act as pioneer factors for others (53,54). Thus, Forkhead box A1 (FoxA1) has been shown to function as a pioneer factor for the estrogen receptor (53,55,56) and the androgen receptor (55,(57)(58)(59), PU.1 has been shown to facilitate C/EBP␤ and LXR binding during macrophage development (40), and C/EBPs and AP-1 have been shown to facilitate glucocorticoid receptor (GR) binding in several different model systems (60)(61)(62)(63). The current study extends cooperative binding of transcription factors to the major regulators of adipocyte differentiation and demonstrates that they can act as mutual pioneer factors for each other.…”

Section: Discussionmentioning

confidence: 99%

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Peroxisome Proliferator-Activated Receptor γ and C/EBPα Synergistically Activate Key Metabolic Adipocyte Genes by Assisted Loading

Madsen

Siersbæk

Boergesen

et al. 2014

Molecular and Cellular Biology

198

144

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Peroxisome proliferator-activated receptor ␥ (PPAR␥) and CCAAT/enhancer binding protein ␣ (C/EBP␣) are key activators of adipogenesis. They mutually induce the expression of each other and have been reported to cooperate in activation of a few adipocyte genes. Recently, genome-wide profiling revealed a high degree of overlap between PPAR␥ and C/EBP␣ binding in adipocytes, suggesting that cooperativeness could be mediated through common binding sites. To directly investigate the interplay between PPAR␥ and C/EBP␣ at shared binding sites, we established a fibroblastic model system in which PPAR␥ and C/EBP␣ can be independently expressed. Using RNA sequencing, we demonstrate that coexpression of PPAR␥ and C/EBP␣ leads to synergistic activation of many key metabolic adipocyte genes. This is associated with extensive C/EBP␣-mediated reprogramming of PPAR␥ binding and vice versa in the vicinity of these genes, as determined by chromatin immunoprecipitation combined with deep sequencing. Our results indicate that this is at least partly mediated by assisted loading involving chromatin remodeling directed by the leading factor. In conclusion, we report a novel mechanism by which the key adipogenic transcription factors, PPAR␥ and C/EBP␣, cooperate in activation of the adipocyte gene program. The conversion of preadipocytes to mature fat-laden adipocytes involves a complex network of transcription factors that have been shown to act in two waves (1-4). The adipogenic cocktail used to stimulate in vitro differentiation of preadipocytes induces the first wave of factors that then subsequently induce the second wave of adipogenic transcription factors. Key components of this second wave are peroxisome proliferator-activated receptor ␥ (PPAR␥) and CCAAT/enhancer binding protein ␣ (C/EBP␣), each of which has been shown to directly promote expression of the adipocyte gene program. In particular, several ex vivo and in vivo studies have demonstrated that PPAR␥ is obligate for adipogenesis (5-7) as well as maintenance of the adipocyte phenotype (8). Similarly, several in vivo models have demonstrated the importance of C/EBP␣ for differentiation and maintenance of white adipose tissue (9-11). C/EBP␣ is also important for ex vivo differentiation of adipocytes, although it is not strictly required for adipocyte differentiation in the presence of ectopic PPAR␥ expression (12). Furthermore, C/EBP␣ has been reported to be specifically involved in activating the gene program driving insulinstimulated glucose uptake (13,14).It is well established that PPAR␥ and C/EBP␣ cooperate to accelerate adipogenesis (12, 15) through their mutual induction of each other (14,(16)(17)(18). In addition, at least some target genes have been shown to be activated by both transcription factors (19-25). More recent genome-wide profiling of C/EBP␣ and PPAR␥ binding sites using chromatin immunoprecipitation (ChIP) combined with microarray analysis (ChIP-chip) or deep sequencing (ChIPseq) have shown that most adipocyte genes in murine adipocytes are associate...

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ and C/EBPα Synergistically Activate Key Metabolic Adipocyte Genes by Assisted Loading

Madsen

Siersbæk

Boergesen

et al. 2014

Molecular and Cellular Biology

198

144

View full text Add to dashboard Cite

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“…Recently, global transcriptom profiling and complex molecular genetics have been used to provide additional understanding of c-Jun (Florin et al, 2004;Wolter et al, 2008;Biddie et al, 2011;Li et al, 2011). It is anticipated that future work, based on sophisticated genetic and molecular approaches, will be instrumental to delineate the multifaceted regulation and functions of c-Jun in vivo.…”

Section: Resultsmentioning

confidence: 99%

c-Jun, at the crossroad of the signaling network

2011

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“…For example, genomewide analysis of GR interactions with DNA (i.e. chromatin-immunoprecipitation of GR followed by deep sequencing, or ChIP-seq) indicated that interactions between GR and inflammatory transcription factors do not necessarily lead to repressive regulatory outcomes (11)(12)(13)(14). Moreover, an increasing number of GR-induced genes are now recognized as contributing to inflammatory repression by GCs (15)(16)(17).…”

mentioning

confidence: 99%

Cistrome-based Cooperation between Airway Epithelial Glucocorticoid Receptor and NF-κB Orchestrates Anti-inflammatory Effects

Kadiyala

Sasse

Altonsy

et al. 2016

Journal of Biological Chemistry

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Antagonism of pro-inflammatory transcription factors by monomeric glucocorticoid receptor (GR) has long been viewed as central to glucocorticoid (GC) efficacy. However, the mechanisms and targets through which GCs exert therapeutic effects in diseases such as asthma remain incompletely understood. We previously defined a surprising cooperative interaction between GR and NF-B that enhanced expression of A20 (TNFAIP3), a potent inhibitor of NF-B. Here we extend this observation to establish that A20 is required for maximal cytokine repression by GCs. To ascertain the global extent of GR and NF-B cooperation, we determined genome-wide occupancy of GR, the p65 subunit of NF-B, and RNA polymerase II in airway epithelial cells treated with dexamethasone, TNF, or both using chromatin immunoprecipitation followed by deep sequencing. We found that GR recruits p65 to dimeric GR binding sites across the genome and discovered additional regulatory elements in which GR-p65 cooperation augments gene expression. GR targets regulated by this mechanism include key anti-inflammatory and injury response genes such as SERPINA1, which encodes ␣1 antitrypsin, and FOXP4, an inhibitor of mucus production. Although dexamethasone treatment reduced RNA polymerase II occupancy of TNF targets such as IL8 and TNFAIP2, we were unable to correlate specific binding sequences for GR or occupancy patterns with repressive effects on transcription. Our results suggest that cooperative anti-inflammatory gene regulation by GR and p65 contributes to GC efficacy, whereas tethering interactions between GR and p65 are not universally required for GC-based gene repression.

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Transcription Factor AP1 Potentiates Chromatin Accessibility and Glucocorticoid Receptor Binding

Cited by 415 publications

References 44 publications

Peroxisome Proliferator-Activated Receptor γ and C/EBPα Synergistically Activate Key Metabolic Adipocyte Genes by Assisted Loading

Peroxisome Proliferator-Activated Receptor γ and C/EBPα Synergistically Activate Key Metabolic Adipocyte Genes by Assisted Loading

c-Jun, at the crossroad of the signaling network

Cistrome-based Cooperation between Airway Epithelial Glucocorticoid Receptor and NF-κB Orchestrates Anti-inflammatory Effects

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