Environment drives selection and function of enhancers controlling tissue-specific macrophage identities

Cell. 2014 Dec 4;159(6):1327-40. doi: 10.1016/j.cell.2014.11.023.


Macrophages reside in essentially all tissues of the body and play key roles in innate and adaptive immune responses. Distinct populations of tissue macrophages also acquire context-specific functions that are important for normal tissue homeostasis. To investigate mechanisms responsible for tissue-specific functions, we analyzed the transcriptomes and enhancer landscapes of brain microglia and resident macrophages of the peritoneal cavity. In addition, we exploited natural genetic variation as a genome-wide "mutagenesis" strategy to identify DNA recognition motifs for transcription factors that promote common or subset-specific binding of the macrophage lineage-determining factor PU.1. We find that distinct tissue environments drive divergent programs of gene expression by differentially activating a common enhancer repertoire and by inducing the expression of divergent secondary transcription factors that collaborate with PU.1 to establish tissue-specific enhancers. These findings provide insights into molecular mechanisms by which tissue environment influences macrophage phenotypes that are likely to be broadly applicable to other cell types.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Enhancer Elements, Genetic*
  • Genetic Variation
  • Histone Code
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Inbred Strains
  • Transcription Factors / metabolism


  • Transcription Factors

Associated data

  • GEO/GSE62826