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

Serena Ghisletti, Iros Barozzi, Flore Mietton, Sara Polletti, Francesca De Santa, Elisa Venturini, Lorna Gregory, Lorne Lonie, Adeline Chew, Chia Lin Wei, Jiannis Ragoussis, Gioacchino Natoli

Research output: Contribution to journalArticlepeer-review


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-κB, 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.

Original languageEnglish
Pages (from-to)317-328
Number of pages12
Issue number3
Publication statusPublished - Mar 2010



ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology


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