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

David Gosselin, Verena M. Link, Casey E. Romanoski, Gregory J. Fonseca, Dawn Z. Eichenfield, Nathanael J. Spann, Joshua D. Stender, Hyun B. Chun, Hannah Garner, Frederic Geissmann, Christopher K. Glass

Research output: Contribution to journalArticlepeer-review

829 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1327-1340
Number of pages14
JournalCell
Volume159
Issue number6
DOIs
StatePublished - Dec 4 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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