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Genome-Wide Approaches to Defining Macrophage Identity and Function

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  • Authors: Gregory J. Fonseca1, Jason S. Seidman2,3, Christopher K. Glass4,5
  • Editor: Siamon Gordon6
    Affiliations: 1: Department of Cellular and Molecular Medicine; 2: Department of Cellular and Molecular Medicine; 3: Biomedical Sciences Graduate Program; 4: Department of Cellular and Molecular Medicine; 5: Department of Medicine, University of California, San Diego, La Jolla, CA 92093; 6: Oxford University, Oxford, United Kingdom
  • Source: microbiolspec September 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.MCHD-0039-2016
  • Received 08 June 2016 Accepted 16 August 2016 Published 30 September 2016
  • Christopher K. Glass, [email protected]
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  • Abstract:

    Macrophages play essential roles in the response to injury and infection and contribute to the development and/or homeostasis of the various tissues they reside in. Conversely, macrophages also influence the pathogenesis of metabolic, neurodegenerative, and neoplastic diseases. Mechanisms that contribute to the phenotypic diversity of macrophages in health and disease remain poorly understood. Here we review the recent application of genome-wide approaches to characterize the transcriptomes and epigenetic landscapes of tissue-resident macrophages. These studies are beginning to provide insights into how distinct tissue environments are interpreted by transcriptional regulatory elements to drive specialized programs of gene expression.

  • Citation: Fonseca G, Seidman J, Glass C. 2016. Genome-Wide Approaches to Defining Macrophage Identity and Function. Microbiol Spectrum 4(5):MCHD-0039-2016. doi:10.1128/microbiolspec.MCHD-0039-2016.


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Macrophages play essential roles in the response to injury and infection and contribute to the development and/or homeostasis of the various tissues they reside in. Conversely, macrophages also influence the pathogenesis of metabolic, neurodegenerative, and neoplastic diseases. Mechanisms that contribute to the phenotypic diversity of macrophages in health and disease remain poorly understood. Here we review the recent application of genome-wide approaches to characterize the transcriptomes and epigenetic landscapes of tissue-resident macrophages. These studies are beginning to provide insights into how distinct tissue environments are interpreted by transcriptional regulatory elements to drive specialized programs of gene expression.

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General organization of enhancers and promoters. DNA is packaged into nucleosomes that are displaced by sequence-specific transcription factors and coactivators. Promoters are primarily occupied by broadly expressed transcription factors, whereas enhancers are enriched for the binding of LDTFs. SDTFs can bind to enhancers or promoters (here shown only at the enhancer). Promoters are distinguished by high levels of H3K4me3 compared to H3K4me1 and H3K4me2. Enhancers are characterized by high levels of H3K4me1 relative to H3K4me3. Active enhancers and promoters are associated with transcriptional coactivators and acetylated histones, such as H3K27ac. Active enhancers are frequently associated with RNA polymerase II (Pol II) enzymes that generate eRNAs.

Source: microbiolspec September 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.MCHD-0039-2016
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Superenhancers (SEs) in macrophages. (A) Venn diagram of shared and subset-specific superenhancers in thioglycolate-elicited macrophages (TGEMs), large peritoneal macrophages (LPMs), and microglia. (B) Examples of subset-specific superenhancers near the and genes in TGEMs, LPMs, and microglia. (C) Partial listing of the 151 genes associated with superenhancers found in all three macrophage subsets. (D) Partial listing of genes associated with the 257 superenhancers selectively found in microglia.

Source: microbiolspec September 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.MCHD-0039-2016
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A collaborative/hierarchical model for selection and activation of macrophage enhancers. Macrophage LDTFs, exemplified by PU.1 and C/EBPs, collaborate with each other to bind to genomic regions containing closely spaced PU.1 and C/EBP recognition motifs to establish a primed enhancer. Signal-dependent activation of NF-κB (here shown as p50 and p65) leads to its binding to primed enhancers and enhancer activation, resulting in histone acetylation and production of eRNAs.

Source: microbiolspec September 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.MCHD-0039-2016
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Selection and activation of tissue-specific macrophage enhancers. (A) Generic model. A core set of macrophage LDTFs, exemplified by PU.1 and C/EBP factors, prime a common set of enhancers in many or all macrophage subsets. These enhancers can be acted upon by environment-specific signals to drive the expression of direct target genes. A subset of these genes includes transcription factors that can collaborate with macrophage LDTFs, such as PU.1, to select a secondary, tissue-specific set of enhancers that drive expression of additional target genes. The tissue-specific gene expression program thus results from both direct and indirect environmental effects. (B) Examples of signals preferential for the peritoneal cavity (retinoic acid) or brain (TGF-β), resulting in expression of collaborative factors Gata6 or SMADs, respectively. MG, microglia.

Source: microbiolspec September 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.MCHD-0039-2016
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