Identification and Characterization of Enhancers Controlling the Inflammatory Gene Expression Program in Macrophages.
Ghisletti, Serena 1,5; Barozzi, Iros 1,5; Mietton, Flore 1,5; Polletti, Sara 1,5; De Santa, Francesca 1; Venturini, Elisa 2; Gregory, Lorna 3; Lonie, Lorne 3; Chew, Adeline 4; Wei, Chia-Lin 4; Ragoussis, Jiannis 3; Natoli, Gioacchino 1,*
[Article] Immunity. 32(3):317-328, March 2010.

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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-[kappa]B, 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.

(C) 2010Elsevier, Inc.