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 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.
Ghisletti
Serena
S
Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16, Milan, Italy.
Barozzi
Iros
I
Mietton
Flore
F
Polletti
Sara
S
De Santa
Francesca
F
Venturini
Elisa
E
Gregory
Lorna
L
Lonie
Lorne
L
Chew
Adeline
A
Wei
Chia-Lin
CL
Ragoussis
Jiannis
J
Natoli
Gioacchino
G
D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D002843:Chromatin / Q000276:immunology / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D002843:Chromatin; D050881:E1A-Associated p300 Protein; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C494361:Ep300 protein, mouse