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Identification and Characterization of Enhancers Controlling the Inflammatory Gene Expression Program in Macrophages

ABSTRACT: Enhancers determine tissue-specific gene expression programs. Enhancers are marked by high histone H3 lysine 4 mono-methylation (H3K4me1) and by the acetyl-transferase p300, which has allowed genome-wide enhancer identification. However, the regulatory principles by which subsets of enhancers become active in specific developmental and/or environmental contexts are unknown. We exploited inducible p300 binding to chromatin to identify, and then mechanistically dissect, enhancers controlling endotoxin-stimulated gene expression in macrophages. In these enhancers, binding sites for the lineage-restricted and constitutive Ets protein PU.1 coexisted with those for ubiquitous stress-inducible transcription factors such as NF-kappaB, IRF, and AP-1. PU.1 was required for maintaining H3K4me1 at macrophage-specific enhancers. Reciprocally, ectopic expression of PU.1 reactivated these enhancers in fibroblasts. Thus, the combinatorial assembly of tissue- and signal-specific transcription factors determines the activity of a distinct group of enhancers. We suggest that this may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE19553 | GEO | 2010/03/05

SECONDARY ACCESSION(S): PRJNA122391

REPOSITORIES: GEO

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Identification and Characterization of Enhancers Controlling the Inflammatory Gene Expression Program in Macrophages

Project description:Enhancers determine tissue-specific gene expression programs. Enhancers are marked by high histone H3 lysine 4 mono-methylation (H3K4me1) and by the acetyl-transferase p300, which has allowed genome-wide enhancer identification. However, the regulatory principles by which subsets of enhancers become active in specific developmental and/or environmental contexts are unknown. We exploited inducible p300 binding to chromatin to identify, and then mechanistically dissect, enhancers controlling endotoxin-stimulated gene expression in macrophages. In these enhancers, binding sites for the lineage-restricted and constitutive Ets protein PU.1 coexisted with those for ubiquitous stress-inducible transcription factors such as NF-kappaB, IRF, and AP-1. PU.1 was required for maintaining H3K4me1 at macrophage-specific enhancers. Reciprocally, ectopic expression of PU.1 reactivated these enhancers in fibroblasts. Thus, the combinatorial assembly of tissue- and signal-specific transcription factors determines the activity of a distinct group of enhancers. We suggest that this may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation. Chromatin immuno-precipitations of p300, PU.1 and mono-methylated H3 lysine 4 followed by multiparallel sequencing were performed in bone marrow-derived macrophages. Experiments for p300 and PU.1 were also carried out in cells treated for 2hrs with lipopolysaccharide (LPS). In case of p300, reads obtained from two different biological replicates were merged.

2010-03-05 | E-GEOD-19553 | biostudies-arrayexpress

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Foxd3 binding at enhancers controls developmental timing of gene expression by regulation of histone acetylation [ChIP-seq]

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2011-12-04 | E-GEOD-33509 | biostudies-arrayexpress

H4K16 acetylation marks active genes and enhancers of embryonic stem cells, but does not alter chromatin compaction (I) [ChIP-Seq]

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A UTX–MLL4–p300 Transcriptional Regulatory Network Coordinately Shapes Active Enhancer Landscapes for Eliciting Transcription (RNA-Seq)

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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