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Environment Drives Selection and Function of Enhancers Controlling Tissue-Specific Macrophage Identities
Open accessAbstract
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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“SPI1, also known as PU.1, binds SMAD3 to establish a homeostatic gene regulatory landscape in microglia 18 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [18]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Transcriptomic analysis of mouse microglia transferred to a tissue culture environment for 7 days documented significant changes in expression of hundreds of genes, with a preferential reduction in expression of microglia-specific genes (25).”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Microglial cells are dynamic and respond quickly to changes in their local environment15.”
From Mouse microglia express unique miRNA-mRNA networks to facilitate age-specific functions in the developing central nervous system (2023) · cites this paper as [15]
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“Most signature genes were downregulated by cells in culture (Fig. 6F), consistent with prior reports (Butovsky et al., 2014; Gosselin et al., 2014).”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Gosselin et al., 2014
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“Our findings that microglia rapidly de-differentiate in culture reecho and expand upon previous reports (Butovsky et al., 2014; Gosselin et al., 2014).”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Gosselin et al., 2014
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“Given the distinct genetic and transcriptomic profile of microglia and macrophages identified via high throughput sequencing technology (69–71), the two cell types likely maintain different roles in the injured central nervous system (CNS) (72–74).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [69]
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In the citing paper
“Microglia also express hundreds of genes at higher levels than other macrophage subsets (24–26) that may be influenced by factors present in the CNS microenvironment (25, 27), suggesting mechanisms by which the brain environment influences the activity and functions of one of its primary support cells.”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [25]
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“Common SEs were associated with genes that are known to play essential roles in the development and function of virtually all macrophages whereas mouse microglia-specific SEs were associated with genes known to play restricted or selected roles in this cell type (25).”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [25]
The cited source says what the claim attributes to it.
In the citing paper
“Microglia also express hundreds of genes at higher levels than other macrophage subsets (24–26) that may be influenced by factors present in the CNS microenvironment (25, 27), suggesting mechanisms by which the brain environment influences the activity and functions of one of its primary support cells.”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [25]
In the citing paper
“During normal CNS function, microglia have a “resting,” or homeostatic, transcriptome profile that reflects a surveilling activity (36–41) (Figure 1).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [38]
In the citing paper
“Analysis of the microglia transcriptome in comparison with that of other tissue macrophages has revealed a strong influence of TGF-β signaling, which culminates in the activation of SMAD proteins that induce transcription of specific target genes, including the purinergic receptor P2Y12 (37, 38, 43).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [38]
In the citing paper
“Motif analysis of PU.1 binding sites has shown enrichment for consensus sequences for mothers against decapentaplegic homologue 3 (SMAD3), myocyte-specific enhancer factor 2A (MEF2A) and transcription factor MafB (MAFB), suggesting that these transcription factors cooperate with PU.1 to establish microglial-specific enhancer profiles75.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [75]
In the citing paper
“These include the SMAD proteins, which are TGFβ1-dependent and contribute to establishing transcription of specific microglial genes75.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [75]
In the citing paper
“References 75 and 76 provide evidence that the tissue environment is a major determinant of resident macrophage gene expression and that PU.1 binds SMAD3 to establish a microglial-specific enhancer profile.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [75]
In the citing paper
“References 75 and 76 provide evidence that the tissue environment is a major determinant of resident macrophage gene expression and that PU.1 binds SMAD3 to establish a microglial-specific enhancer profile.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [75]
In the citing paper
“Furthermore, four binding motifs Mafb, Stat3, Usf1, and Smad2 were preferentially associated with PU.1 binding specifically in microglia in mice, suggesting these transcription factors are microglia-specific co-regulators that cooperate with PU.1 for establishing microglia-specific gene enhancer profiles [5].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [5]
In the citing paper
“suggesting these transcription factors are microglia-specific co-regulators that cooperate with PU.1 for establishing microglia-specific gene enhancer profiles [5].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [5]
In the citing paper
“Microglial transcriptomes are tightly regulated by multiple key transcription factors such as Sall1, Spi1, Mafb, and Mef2c [5, 15].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [5]
In the citing paper
“Microglia development is largely controlled by the transcription factors IRF8 and PU.1.”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [5]
In the citing paper
“Microglial dysfunction contributes to the pathogenesis of neurodegenerative disorders including Alzheimer’s disease (AD) and neurodevelopmental disorders including autism spectrum disorder and schizophrenia [5-7].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [5]
In the citing paper
“In addition to FACS and immunohistochemical approaches, assay for transposase accessible chromatin sequencing (ATAC-seq) can evaluate transcriptional networks that control microglial signature at an epigenetic level determining the chromatin accessibility landscape in microglia [5, 22, 23].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [5]
In the citing paper
“The microglia-enriched PU.1 binding regions were also enriched with Smad, Mef2, and Ctcfl family-binding motifs, identifying interactions between the transcription factors [5].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [5]
In the citing paper
“Microglia culture models have been developed to recapitulate microglia in vivo, but have multiple limitations.”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [5]
In the citing paper
“Microglia lose their distinct expression patterns once cultured in vitro [5, 22].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [5]
In the citing paper
“These data implicate these factors in modulating promoter/enhancer regions that enables appropriate responses to stimuli previously shown for macrophages”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Gosselin et al., 2014
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Metadata
- Authors
- Gosselin, D., Link, V. M., Romanoski, C. E., Fonseca, G. J., Eichenfield, D. Z., Spann, N. J., Stender, J. D., Chun, H. B., Garner, H., Geissmann, F., & Glass, C. K.
- Affiliations
- University of California San Diego (US)
- King's College London (GB)
- Corresponding author
- Glass, Christopher K.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 159
- Issue
- 6
- Pages
- 1327-1340
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4364385
- OpenAlex
- W2163774748
- Cited by
- 1,307
- References
- 56
- Citations by year
- 2026: 77 · 2025: 84 · 2024: 91 · 2023: 92 · 2022: 106 · 2021: 133 · 2020: 145 · 2019: 117 · 2018: 120 · 2017: 129 · 2016: 120 · 2015: 91
- FWCI
- 46.44
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-01-15)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- American Heart Association
- Wellcome Trust (WT101853MA, 101853)
- National Institutes of Health
- University of California, San Diego
- Canadian Institutes of Health Research
- Biotechnology and Biological Sciences Research Council (1168004)
- National Heart, Lung, and Blood Institute (K99HL123485, 1K99HL12348, P01HL088093)
- National Cancer Institute (R01CA173903, R01CA052599, P30CA023100, CA17390)
- National Institute of General Medical Sciences (GM 085764, P50GM085764, T32GM007198)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, DK091183, P01DK074868, P30DK063491, R01DK091183)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tissue-specific macrophages, enhancers, microglia, peritoneal macrophages, PU.1, transcription factor binding motifs, natural genetic variation, tissue environment, gene expression regulation
- MeSH terms
- Animals, Enhancer Elements, Genetic, Macrophages, Male, Mice, Inbred C57BL, Mice, Inbred Strains, Transcription Factors, Genetic Variation, Mice, Inbred NOD, Histone Code
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