Identification of enhancer regulating Il9 gene
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE106404 | GEO | 2018/10/01
REPOSITORIES: GEO
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Project description:Signaling pathways are intimately involved in cellular differentiation, allowing cells to respond to their environment by regulating gene expression. While enhancers are recognized as key elements that regulate selective gene expression, the interplay between signaling pathways and actively used enhancer elements is not clear. Here, we use CD4+ T cells as a model of differentiation, mapping the acquisition of cell-type-specific enhancer elements in T-helper 1 (Th1) and Th2 cells. Our data establish that STAT proteins have a major impact on the acquisition of lineage-specific enhancers and the suppression of enhancers associated with alternative cell fates. Transcriptome analysis further supports a functional role for enhancers regulated by STATs. Importantly, expression of lineage-defining master regulators in STAT-deficient cells fails to fully recover the chromatin signature of STAT-dependent enhancers. Thus, these findings point to a critical role of STATs as environmental sensors in dynamically molding the specialized enhancer architecture of differentiating cells. Active enhancer elements were defined as p300-high/H3K4me1-high. Using ChIP-seq, we mapped active enhancer landscapes of two CD4+ T helper cells, Th1 and Th2. To investigate the effect of STAT proteins on this landscape, we profiled active enhancers in the absence of STATs. Overall, STATs deficiency had a major impact on recruitment of p300. In addition, ectopic expression of master regulators T-bet and GATA3 in STAT-deficient cells failed to recover most active enhancers.
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Project description:Th cell differentiation is transcriptionally regulated, relying on the induction of “lineage-defining” transcription factors. We report that formation of super-enhancers is critical in robust induction of Th9 cells and that assembly of the Il9 super-enhancers requires OX40-triggered chromatin H3K27 acetylation. Mechanistically, we found that OX40 costimulation induces RelB expression, which recruits the histone acetyltransferase p300 to the Il9 locus to catalyze H3K27 acetylation. This allows binding of the super-enhancer factor Brd4 to initiate assembly of the super-enhancer complex, which in turn drives robust Th9 induction. Thus, Th9 cells are induced in massive numbers upon OX40 costimulation and disruption of super-enhancers abolished Th9 induction in vitro and inhibited Th9-mediated allergic airway inflammation in vivo. Our data identify super-enhancers as a key mechanism of Th9 induction and uncover a new mechanism of Th cell differentiation.
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Project description:Identificaiton of enhancer regulating Il9 gene
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Project description:Estrogen receptors alpha (ERα) converges estrogen signaling by orchestrating estrogen (E2)-dependent transcription regulation. Upon binding to the chromatin, ERα serves as a nucleation site for de novo formation of transcription enhancer complexes. Steroid receptor coactivators family proteins (SRCs, a.k.a p160) and Mediator complex are the two coregulators for ERα that directly interact with the receptors and control enhancer activity by regulating recruitment of other coregulators and transcription machinery. Lysine acetyltransferase p300/CBP is also a critical coregulator for ERα that is recruited through SRCs in stable ERα enhancer complex. ERα enhancers exhibit common enhancer features including enrichment of enhancer-specific histone modification (e.g. H3K4me1 and H3K27ac), coregulator recruitment, and active transcription. Despite of recognition of those enhancer characteristics, the order of assembly and functions and the functional relationships among enhancer features during active enhancer complex formation is not well understood. Using the time course genomics and molecular biology assays, we dissect the order of assembly and functions of ERα enhancer complex formation. We describe the mechanism of SRC-independent p300 recruitment mediated by Mediator, leading to initial partial activation of the ERα enhancer for enhance priming. Maturation of the enhancer in turn switches the p300 recruitment mechanism to an SRC-dependent manner, resulting in the maximum enhancer activity and transcription outcomes. Thus, our results illustrate the role of SRC in enhancing the activity of primed enhancers. Furthermore, we show that forced recruitment of p300 to inactive enhancers establishes active enhancer marks and induces ERα-target gene expression. Together, we demonstrate the molecular mechanisms of ERα enhancer complex formation where p300 plays a pivotal role in enhancer activation and target gene expression controlled by distinctive mechanisms through different stages of ERα enhancer complex formation.
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Project description:Signaling pathways are intimately involved in cellular differentiation, allowing cells to respond to their environment by regulating gene expression. While enhancers are recognized as key elements that regulate selective gene expression, the interplay between signaling pathways and actively used enhancer elements is not clear. Here, we use CD4+ T cells as a model of differentiation, mapping the acquisition of cell-type-specific enhancer elements in T-helper 1 (Th1) and Th2 cells. Our data establish that STAT proteins have a major impact on the acquisition of lineage-specific enhancers and the suppression of enhancers associated with alternative cell fates. Transcriptome analysis further supports a functional role for enhancers regulated by STATs. Importantly, expression of lineage-defining master regulators in STAT-deficient cells fails to fully recover the chromatin signature of STAT-dependent enhancers. Thus, these findings point to a critical role of STATs as environmental sensors in dynamically molding the specialized enhancer architecture of differentiating cells.
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Project description:Enhancer activation is a critical step for gene activation. Here we report a novel epigenetic crosstalk at enhancers between the UTX (H3K27 demethylase)-MLL4 (H3K4 methyltransferase) complex and the histone acetyltransferase p300. We demonstrate that UTX, in a demethylase activity-independent manner, facilitates conversion of naïve (unmarked) enhancers in embryonic stem cells to an active (H3K4me1+/H3K27ac+) state by recruiting and coupling the enzymatic functions of MLL4 and p300. Loss of UTX leads to attenuated enhancer activity, characterized by reduced levels of H3K4me1 and H3K27ac as well as impaired transcription. The UTX-MLL4 complex enhances p300-dependent H3K27 acetylation through UTX-dependent stimulation of p300 recruitment while MLL4-mediated H3K4 monomethylation, reciprocally, requires p300 function. Importantly, MLL4-generated H3K4me1 further enhances p300-dependent transcription. This work reveals a previously unrecognized cooperativity among enhancer-associated chromatin modulators, including a unique function for UTX, in establishing an “active enhancer landscape” and defines a mechanism for the joint deposition of H3K4me1 and H3K27ac.
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