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

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

Author information

1
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
2
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA; Faculty of Biology, Department II, Ludwig-Maximilians Universität München, Planegg-Martinsried 82152, Germany.
3
Centre for Molecular and Cellular Biology of Inflammation, King's College London, London SE1 1UL, UK; Peter Gorer Department of Immunobiology, King's College London, London SE1 1UL, UK.
4
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA; Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA. Electronic address: ckg@ucsd.edu.

Abstract

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.

PMID:
25480297
PMCID:
PMC4364385
DOI:
10.1016/j.cell.2014.11.023
[Indexed for MEDLINE]
Free PMC Article

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