Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages

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...

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Published in:Immunity (Cambridge, Mass.) Vol. 32; no. 3; p. 317
Main Authors: Ghisletti, Serena, Barozzi, Iros, Mietton, Flore, Polletti, Sara, De Santa, Francesca, Venturini, Elisa, Gregory, Lorna, Lonie, Lorne, Chew, Adeline, Wei, Chia-Lin, Ragoussis, Jiannis, Natoli, Gioacchino
Format: Journal Article
Language:English
Published: United States 26.03.2010
Subjects:
Animals
Binding Sites
Cells, Cultured
Chromatin - immunology
Chromatin - metabolism
E1A-Associated p300 Protein - genetics
E1A-Associated p300 Protein - metabolism
Female
Gene Expression Profiling
Gene Expression Regulation
Inflammation - genetics
Inflammation - immunology
Inflammation - metabolism
Lipopolysaccharides - immunology
Macrophages - immunology
Macrophages - metabolism
Mice
Protein Binding
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Regulatory Sequences, Nucleic Acid
Trans-Activators - genetics
Trans-Activators - metabolism
ISSN:1097-4180, 1097-4180
Online Access:Get more information
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Summary: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.
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ISSN:1097-4180
1097-4180
DOI:10.1016/j.immuni.2010.02.008