title: Environment drives selection and function of enhancers controlling tissue-specific macrophage identities.
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.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gosselin
authors.affiliation: 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.
authors.forename: Verena M
authors.initials: VM
authors.lastname: Link
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
authors.forename: Casey E
authors.initials: CE
authors.lastname: Romanoski
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Fonseca
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
authors.forename: Dawn Z
authors.initials: DZ
authors.lastname: Eichenfield
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
authors.forename: Nathanael J
authors.initials: NJ
authors.lastname: Spann
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Stender
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
authors.forename: Hyun B
authors.initials: HB
authors.lastname: Chun
authors.affiliation: 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.
authors.forename: Hannah
authors.initials: H
authors.lastname: Garner
authors.affiliation: 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.
authors.forename: Frederic
authors.initials: F
authors.lastname: Geissmann
authors.affiliation: 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.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
mesh_terms: D000818:Animals; D004742:Enhancer Elements, Genetic; D014644:Genetic Variation; D042421:Histone Code; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors