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 (PU.1) binds SMAD3 to establish a homeostatic gene regulatory landscape in microglia.
“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]
The Results sections on PU.1 co-localization and natural genetic variation (pages not provided) report that SMAD motifs, including a SMAD3 recognition motif, are associated with PU.1 binding at microglia-specific sites. They do not demonstrate that PU.1 directly binds SMAD3 or establish that this interaction creates a homeostatic gene regulatory landscape. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMost microglial signature genes are downregulated in culture.
“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
Microglia rapidly de-differentiate in culture.
“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
Given the distinct genetic and transcriptomic profile of microglia and macrophages identified via high throughput sequencing technology, the two cell types likely maintain different roles in the injured CNS.
“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]
During normal CNS function, microglia have a resting or homeostatic transcriptome profile that reflects a surveilling activity.
“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]
Analysis of the microglia transcriptome compared with other tissue macrophages revealed a strong influence of TGF-β signaling, culminating in SMAD activation that induces transcription of specific target genes including P2Y12.
“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]
PU.1 binding sites are enriched for SMAD3, MEF2A, and MAFB consensus sequences, suggesting these factors cooperate with PU.1 to establish microglial-specific enhancer profiles.
“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]
SMAD proteins are TGFβ1-dependent and contribute to establishing transcription of specific microglial genes.
“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]
The local tissue environment is a major determinant of the gene expression of resident macrophages.
“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]
PU.1 binds SMAD3 in order to establish an enhancer profile specific to microglia.
“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]
Mafb, Stat3, Usf1, and Smad2 motifs are preferentially associated with PU.1 binding specifically in mouse microglia.
“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]
Mafb, Stat3, Usf1, and Smad2 are microglia-specific co-regulators that cooperate with PU.1 to establish microglia-specific enhancer profiles.
“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]
Microglial transcriptomes are tightly regulated by multiple key transcription factors such as Sall1, Spi1, Mafb, and Mef2c.
“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]
Microglia development is largely controlled by the transcription factors IRF8 and PU.1.
“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]
Microglial dysfunction contributes to the pathogenesis of neurodegenerative disorders including Alzheimer's disease and neurodevelopmental disorders including autism spectrum disorder and schizophrenia.
“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]
ATAC-seq can evaluate transcriptional networks controlling the microglial signature at an epigenetic level by determining chromatin accessibility.
“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]
Microglia-enriched PU.1 binding regions are enriched with Smad, Mef2, and Ctcfl family-binding motifs, indicating interactions between these transcription factors.
“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]
Microglia culture models were created to mimic microglia in vivo but have several limitations.
“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]
Once placed in culture, microglia lose their characteristic expression patterns.
“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]
CD200 and CX3CL1 likely act on promoter or enhancer regions to allow responses to stimuli previously seen in macrophages.
“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
Microglia express hundreds of genes at higher levels than other macrophage subsets.
“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]
Common super-enhancers are associated with genes that play essential roles in the development and function of virtually all macrophages, whereas mouse microglia-specific super-enhancers are associated with genes known to play restricted or selected roles in this cell type.
“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]
Microglia gene expression may be influenced by factors present in the central nervous system microenvironment.
“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]
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.
“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]
Microglial cells are dynamic and respond quickly to changes in their local environment.
“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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Microglia Function in the Central Nervous System During Health and Neurodegeneration
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Microglia emerge as central players in brain disease
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Microglia Biology: One Century of Evolving Concepts
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Microglia in physiology and disease
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Microglia development follows a stepwise program to regulate brain homeostasis
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Microglial brain region-dependent diversity and selective regional sensitivities to aging
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An environment-dependent transcriptional network specifies human microglia identity
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Self-citationMicroglial signatures and their role in health and disease
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iPSC-derived human microglia-like cells to study neurological diseases
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Innate immune memory in the brain shapes neurological disease hallmarks
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The selection and function of cell type-specific enhancers
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Self-citationOverview of General and Discriminating Markers of Differential Microglia Phenotypes
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Specification of tissue-resident macrophages during organogenesis
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Self-citationDissecting Immune Circuits by Linking CRISPR-Pooled Screens with Single-Cell RNA-Seq
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Self-citationMicrobiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner
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Transcriptomic analysis of purified human cortical microglia reveals age-associated changes
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Regulation of macrophage development and function in peripheral tissues
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Monocyte-macrophages and T cells in atherosclerosis
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Macrophages in health and disease
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Sall1 is a transcriptional regulator defining microglia identity and function
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New insights on the role of microglia in synaptic pruning in health and disease
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A new fate mapping system reveals context-dependent random or clonal expansion of microglia
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Abandoning M1/M2 for a Network Model of Macrophage Function
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A combination of ontogeny and CNS environment establishes microglial identity
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Establishment and Maintenance of the Macrophage Niche
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Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39
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Determinants of resident tissue macrophage identity and function
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Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology
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Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer
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Microbiome–microglia connections via the gut–brain axis
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“The adult microglia transcriptome overlaps with, but is distinct from, other tissue-resident macrophages and is characterized by expression of microglial-specific markers, including Sall1, P2ry12, Gpr84, and Tmem119 (Hickman et al., 2013; Butovsky et al., 2014; Gosselin et al., 2014; Matcovitch-Natan et al., 2016).”
BackgroundSelf-citationModeling Alzheimer’s disease with iPSC-derived brain cells
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Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program
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CD22 blockade restores homeostatic microglial phagocytosis in ageing brains
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Self-citationThe Genetics of Transcription Factor DNA Binding Variation
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Self-citationAryl hydrocarbon receptor Controls Monocyte Differentiation into dendritic Cells versus Macrophages
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The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication
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Microglial Physiology and Pathophysiology: Insights from Genome-wide Transcriptional Profiling
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Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?
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Microglia Versus Myeloid Cell Nomenclature during Brain Inflammation
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Langerhans cells - the macrophage in dendritic cell clothing
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The choreography of neuroinflammation in Huntington's disease
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Self-citationLineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells
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Macrophages in age-related chronic inflammatory diseases
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Tissue-resident macrophages are locally programmed for silent clearance of apoptotic cells
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Immunosenescence of microglia and macrophages: impact on the ageing central nervous system
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Microglia in Brain Development, Homeostasis, and Neurodegeneration
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Does tissue imprinting restrict macrophage plasticity?
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Transcriptional control of microglia phenotypes in health and disease
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Re-evaluating microglia expression profiles using RiboTag and cell isolation strategies
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APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints
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“In brains from females with AD that carry the APOE4 allele, PU.1 expression was associated with increased SMAD3 expression levels, which would reinforce the microglial homeostatic signature as a downstream molecule of TGFβ signaling 13,18,49 .”
BackgroundMicroglial immune checkpoint mechanisms
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PU.1 controls fibroblast polarization and tissue fibrosis
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TREM2 dependent and independent functions of microglia in Alzheimer’s disease
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BIN1 favors the spreading of Tau via extracellular vesicles
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A Binary Cre Transgenic Approach Dissects Microglia and CNS Border-Associated Macrophages
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Periodontal microorganisms and Alzheimer disease – A causative relationship?
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Single-Cell Genomics: A Stepping Stone for Future Immunology Discoveries
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The heterogeneity of lung macrophages in the susceptibility to disease
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Myeloid cell heterogeneity in cancer: not a single cell alike
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Stromal cues regulate the pancreatic cancer epigenome and metabolome
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Transcriptional profiling of microglia; current state of the art and future perspectives
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Epigenetic Changes in Diabetes and Cardiovascular Risk
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Transcriptional and Epigenetic Regulation of Microglia in Health and Disease
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Differential Location and Distribution of Hepatic Immune Cells
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The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease
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Targeting innate immunity for neurodegenerative disorders of the central nervous system
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<i>Cx3cr1-</i> deficient microglia exhibit a premature aging transcriptome
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- 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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