Environment Drives Selection and Function of Enhancers Controlling Tissue-specific Macrophage Identities

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2014 Dec 7

PMID 25480297

Citations 705

Authors

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

Affiliations

Soon will be listed here.

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.

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References

Ostuni R, Piccolo V, Barozzi I, Polletti S, Termanini A, Bonifacio S . Latent enhancers activated by stimulation in differentiated cells. Cell. 2013; 152(1-2):157-71. DOI: 10.1016/j.cell.2012.12.018. View

Hnisz D, Abraham B, Lee T, Lau A, Saint-Andre V, Sigova A . Super-enhancers in the control of cell identity and disease. Cell. 2013; 155(4):934-47. PMC: 3841062. DOI: 10.1016/j.cell.2013.09.053. View

Loven J, Hoke H, Lin C, Lau A, Orlando D, Vakoc C . Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013; 153(2):320-34. PMC: 3760967. DOI: 10.1016/j.cell.2013.03.036. View

Wang Y, Szretter K, Vermi W, Gilfillan S, Rossini C, Cella M . IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol. 2012; 13(8):753-60. PMC: 3941469. DOI: 10.1038/ni.2360. View

Kaikkonen M, Spann N, Heinz S, Romanoski C, Allison K, Stender J . Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell. 2013; 51(3):310-25. PMC: 3779836. DOI: 10.1016/j.molcel.2013.07.010. View

Paolicelli R, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P . Synaptic pruning by microglia is necessary for normal brain development. Science. 2011; 333(6048):1456-8. DOI: 10.1126/science.1202529. View

Zhu Y, Sun L, Chen Z, Whitaker J, Wang T, Wang W . Predicting enhancer transcription and activity from chromatin modifications. Nucleic Acids Res. 2013; 41(22):10032-43. PMC: 3905895. DOI: 10.1093/nar/gkt826. View

Ghisletti S, Barozzi I, Mietton F, Polletti S, De Santa F, Venturini E . Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity. 2010; 32(3):317-28. DOI: 10.1016/j.immuni.2010.02.008. View

Barozzi I, Simonatto M, Bonifacio S, Yang L, Rohs R, Ghisletti S . Coregulation of transcription factor binding and nucleosome occupancy through DNA features of mammalian enhancers. Mol Cell. 2014; 54(5):844-857. PMC: 4048654. DOI: 10.1016/j.molcel.2014.04.006. View

10.

Geissmann F, Manz M, Jung S, Sieweke M, Merad M, Ley K . Development of monocytes, macrophages, and dendritic cells. Science. 2010; 327(5966):656-61. PMC: 2887389. DOI: 10.1126/science.1178331. View

11.

Gautier E, Ivanov S, Williams J, Huang S, Marcelin G, Fairfax K . Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival. J Exp Med. 2014; 211(8):1525-31. PMC: 4113942. DOI: 10.1084/jem.20140570. View

12.

Jung S, Aliberti J, Graemmel P, Sunshine M, Kreutzberg G, Sher A . Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol. 2000; 20(11):4106-14. PMC: 85780. DOI: 10.1128/MCB.20.11.4106-4114.2000. View

13.

Dobin A, Davis C, Schlesinger F, Drenkow J, Zaleski C, Jha S . STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2012; 29(1):15-21. PMC: 3530905. DOI: 10.1093/bioinformatics/bts635. View

14.

Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M . An atlas of active enhancers across human cell types and tissues. Nature. 2014; 507(7493):455-461. PMC: 5215096. DOI: 10.1038/nature12787. View

15.

Yamamoto M, Okuyama M, Ma J, Kimura T, Kamiyama N, Saiga H . A cluster of interferon-γ-inducible p65 GTPases plays a critical role in host defense against Toxoplasma gondii. Immunity. 2012; 37(2):302-13. DOI: 10.1016/j.immuni.2012.06.009. View

16.

Gautier E, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S . Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol. 2012; 13(11):1118-28. PMC: 3558276. DOI: 10.1038/ni.2419. View

17.

Okabe Y, Medzhitov R . Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell. 2014; 157(4):832-44. PMC: 4137874. DOI: 10.1016/j.cell.2014.04.016. View

18.

Andrews N . The NF-E2 transcription factor. Int J Biochem Cell Biol. 1998; 30(4):429-32. DOI: 10.1016/s1357-2725(97)00135-0. View

19.

Creyghton M, Cheng A, Welstead G, Kooistra T, Carey B, Steine E . Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010; 107(50):21931-6. PMC: 3003124. DOI: 10.1073/pnas.1016071107. View

20.

Whyte W, Orlando D, Hnisz D, Abraham B, Lin C, Kagey M . Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013; 153(2):307-19. PMC: 3653129. DOI: 10.1016/j.cell.2013.03.035. View