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Cited by 135Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesNeurological Disease Mechanisms and Treatments

Transcriptional and Epigenetic Regulation of Microglia in Health and Disease

Open access
Yeh, Hana, Ikezu, Tsuneya·2019·Trends in Molecular Medicine
DOI 10.1016/j.molmed.2018.11.004PMC PMC6377292
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Abstract

Microglia are the resident immune cells that maintain brain homeostasis and contribute to neurodegenerative disorders. Recent studies of microglia at transcriptomic and epigenetic levels revealed specific molecular pathways that regulate microglia development, maturation and reactive states. The transcriptionfactor PU.1 plays a key role in regulating several microglial functions. Environmental factors such as microbiota, early life stress and maternal immune activation can dysregulate PU.1 and innate immune response. This review discusses the epigenetic regulation of key transcriptional factors in human and murine microglia, highlighting their networks for shaping the microglial function. PU.1 and other microglia-specific transcriptional factors can be further studied to determine their therapeutic applications in neurologic disorders.

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Written from the paper’s full text.

TL;DR

This review summarizes how transcriptional and epigenetic mechanisms, especially the transcription factor PU.1, regulate microglial development, homeostasis, and reactive states in health and disease. It highlights environmental influences such as microbiota, maternal immune activation, aging, and neurodegeneration on microglial transcriptomes and enhancer landscapes.

Key findings

  • PU.1 is a master regulator of microglial identity and survival: ChIP-seq in BV2 cells showed about 63% of microglial sensome genes are PU.1 targets, and PU.1-deficient mice have reduced expression of Csf1r, Csf2r, and Csf3r.
  • Silencing PU.1 in human microglia reduced microglial number, ramification, and phagocytosis of amyloid-beta peptide 1–42 (AB42), and suppressed DAP12/TYROBP, TREM2, LST1, CD11b, MRC1, CEBPA, PTPRC, and MHC class II genes HLA-DR, HLA-DP, and HLA-DQ.
  • Environmental perturbations alter PU.1 and microglial states: germ-free mice show upregulated PU.1 and CSF1R; maternal immune activation by polyI:C reduces PU.1 and target sensome genes, restored by minocycline; early life stress reduces PU.1 transcriptional activity.
  • In aging and disease, microglial transcriptomes shift: aged microglia downregulate sensome genes such as Trem2, Gpr34, P2ry12, Fcrl1, and Dap12 and upregulate microbe recognition/host defense genes such as Tlr2, Cd74, Ltf, Clec7a, and Cxcl16; disease-associated microglia involve TREM2–APOE and C3–C3aR pathways.

Methods

  • Design: narrative review of transcriptional and epigenetic regulation of microglia in human and murine systems.
  • Data: synthesis of cited transcriptomic, epigenomic, and functional studies, including RNA-seq, ATAC-seq, ChIP-seq, single-nuclei RNA-seq, proteomics, and microglial culture/iPSC-derived models.
  • Main analysis: qualitative integration of findings on PU.1, other transcription factors (SALL1, MEF2, MAFB, IRF8, RUNX1), epigenetic regulators (HDACs, MECP2, H3K4me, H3K27me3, miRNAs), and environmental/disease contexts.

Limitations

  • The paper states that RNA-seq and ChIP-seq are powerful but limited, and that future work should move toward single-cell transcriptomics because current data are largely bulk sequencing; single-cell RNA and ChIP sequencing may have significant limitations in sequencing depth.
  • The paper states that microglia lose distinct expression patterns in vitro, that primary human microglia remain poorly characterized due to limited accessibility and lack of standardized isolation/culture methods, and that human–mouse microglial transcriptome discrepancies need further study.
  • Evident from the text: as a narrative review, it does not report a systematic search strategy, inclusion criteria, or quantitative synthesis; many conclusions depend on cited mouse models and in vitro systems, with remaining mechanistic uncertainty noted for microbiota effects and PU.1 function in dysregulated microglia.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.molmed.2018.11.004

Cites

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Statistics

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Claims the paper makes

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    During development, microglia modulate synapse formation and elimination, shaping brain circuitry.

    “During development, they modulate synapse formation and elimination, revealing microglia’s role in shaping the brain circuitry [4].”
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  • Premisecitation

    Gosselin et al. reported that the PU.1 transcriptional network is the most abundantly expressed ETS domain transcription factor in both murine and human microglia.

    “Using this approach, Gosselin et al. reported PU.1 transcriptional network as the most abundantly expressed ETS domain transcription factor in both murine and human microglia [22].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Premisecitation

    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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    In mice, microglia undergo a step-wise maturation program synchronized with brain developmental phases.

    “In mice, microglia undergo a step-wise program of maturation that is synchronized with the developmental phases of the brain [13, 14]”
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  • Premisecitation

    RNA-sequencing studies identified Siglech as a microglia-specific gene involved in innate immune cell differentiation.

    “RNA-sequencing studies have identified microglia-specific genes such as olfactomedin-like protein 3 (Olfml3), which is involved in early development patterning, and sialic acid binding Ig-like lectin H (Siglech), which is involved in innate immune cell differentiation [10].”
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    Premisecitation

    Under physiological conditions, microglia monitor their surroundings, respond to perturbations, clear cell debris, and regulate synaptic transmission.

    “Under physiological conditions, microglia actively monitor their surroundings, respond to perturbations, clear cell debris, and regulate synaptic transmission [3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Microglia support neuronal functions and networks in addition to maintaining brain homeostasis.

    “Microglia support neuronal functions and networks in addition to maintaining brain homeostasis [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Crotti A and Ransohoff RM, Microglial Physiology and Pathophysiology: Insights from Genome-wide Transcriptional Profiling. Immunity, 2016 44(3): p. 505– 515. 26982357 source

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    Premisecitation

    Microglia originate from the embryonic yolk sac and belong to a lineage separate from bone marrow-derived myeloid cells.

    “Microglia share several markers with monocytes, but are derived from the embryonic yolk sac and have distinct lineage from bone marrow-derived myeloid cells [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    In neurodevelopmental disorders, microglia can have impaired pruning or secrete molecules that contribute to CNS hyperactivity.

    “Although not as clear in neurodevelopmental disorder, microglia can have impaired pruning or secrete molecules that contribute to hyperactivity in the CNS [7, 9].”
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    Premisecitation

    CD38+ resident myeloid cells called CNS border-associated macrophages are embryonically derived and line the meninges, choroid plexus, and perivascular spaces.

    “In addition to microglia, new CD38+ resident myeloid cells called CNS border-associated macrophages (BAMs) are embryonically-derived cells that line along the meninges, choroid plexus, and perivascular spaces [20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Gosselin D,, Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell, 2014 159(6): p. 1327– 1340. 25480297 PMC4364385 source

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    • cites [6] Hong S,, Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science (New York, N.Y.), 2016 352(6286): p. 712– 716. PMC5094372 27033548 source

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    • cites [7] Sekar A,, Schizophrenia risk from complex variation of complement component 4. Nature, 2016 530(7589): p. 177– 183. 26814963 PMC4752392 source

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    Premisecitation

    In neurodegenerative states, microglia can enhance neuroinflammation, leading to more cell deaths.

    “In neurodegenerative state, microglia can enhance neuroinflammation leading to more cell deaths [6, 8].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Hong S,, Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science (New York, N.Y.), 2016 352(6286): p. 712– 716. PMC5094372 27033548 source

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    • cites [8] Hansen DV, Hanson JE, and Sheng M, Microglia in Alzheimer’s disease. The Journal of Cell Biology, 2018 217(2): p. 459. 29196460 PMC5800817 source

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    Premisecitation

    Both microglia and BAMs are CD11b+/CD45low, making them difficult to distinguish without localization patterns.

    “Both microglia and BAMs are CD11b+/CD45low, making it difficult to distinguish between them without localization patterns.”
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    • cites [20] Goldmann T,, Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat Immunol, 2016 17(7): p. 797– 805. 27135602 PMC4968048 source

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    Premisecitation

    PU.1 binds to purine-rich PU-box sequences and activates gene expression during immune cell development.

    “PU.1 binds to purine-rich sequence (PU-box) and activates gene expression during immune cell development [24, 25].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Butovsky O,, Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci, 2014 17(1): p. 131– 43. 24316888 PMC4066672 source

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    Premisecitation

    MECP2-deficient microglia have impaired glutamate synthesis and mitochondrial function.

    “MECP2-deficient microglia have impaired glutamate synthesis and mitochondria function [40].”
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    • cites [40] Jin L-W,, Dysregulation of Glutamine Transporter SNAT1 in Rett Syndrome Microglia: A Mechanism for Mitochondrial Dysfunction and Neurotoxicity. The Journal of Neuroscience, 2015 35(6): p. 2516. 25673846 PMC4323531 source

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    Premisecitation

    Vorinostat treatment reduced DAP12 expression, whereas CD45 and HLA-DR, HLA-DP, or HLA-D1 expression remained unchanged.

    “However, vorinostat treatment showed reduction in DAP12 expression, whereas expression of CD45 and HLA-DR, HLA-DP or HLA-D1 remained unchanged [30].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Rustenhoven J,, PU.1 regulates Alzheimer's disease-associated genes in primary human microglia. Mol Neurodegener, 2018 13(1): p. 44. 30124174 PMC6102813 source

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    Interpretationcitation

    PU.1 has a role in antigen presentation and pro-inflammatory response.

    “suggesting its role in antigen presentation and pro-inflammatory response by PU.1 [30, 31].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [30] Rustenhoven J,, PU.1 regulates Alzheimer's disease-associated genes in primary human microglia. Mol Neurodegener, 2018 13(1): p. 44. 30124174 PMC6102813 source

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    • cites [31] Huang KL,, A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease. Nat Neurosci, 2017 20(8): p. 1052– 1061. 28628103 PMC5759334 source

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    Premisecitation

    ChIP-seq analysis revealed that Mecp2 deletion increased histone acetylation at enhancer regions of Fkbp5 and recruited NCOR2 and HDAC3 complex.

    “Further examination with ChIP-seq analysis revealed that Mecp2-deletion increased histone acetylation at enhancer regions of Fkbp5, a canonical glucocorticoid target gene, and recruitment of nuclear receptor co-repressor2 (NCOR2) and HDAC3 complex [17].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Cronk James C.,, Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli. Immunity, 2015 42(4): p. 679– 691. 25902482 PMC4407145 source

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    Premisecitation

    Global loss of Mecp2 reduces numbers of microglia, perivascular meningeal macrophages, intestinal macrophages, and LY6Clo circulating monocytes.

    “Global loss of Mecp2 leads to reduced numbers of microglia, perivascular meningeal macrophages, intestinal macrophages and LY6Clo circulating monocytes [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Cronk James C.,, Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli. Immunity, 2015 42(4): p. 679– 691. 25902482 PMC4407145 source

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    Interpretationcitation

    Mecp2 deletion dysregulates genes involved in glucocorticoid signaling, hypoxia response, and inflammatory responses.

    “These results show dysregulation of genes involved in glucocorticoid signaling, hypoxia response and inflammatory responses, suggesting Mecp2 is critical for maintaining immune cell function including microglia [17].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Cronk James C.,, Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli. Immunity, 2015 42(4): p. 679– 691. 25902482 PMC4407145 source

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  • May combine two claims.

    Interpretationreasoning

    PU.1 acts as a master regulator controlling development and maintenance of homeostatic microglial functions, including CSF1R-mediated survival, phagocytosis, antigen presentation, and ramified morphology.

    “In vitro and in vivo studies show that PU.1 act as a master regulator and controls the development and maintenance of homeostatic function in microglia, such as CSF1R-mediated cell survival, phagocytosis, antigen presentation, and ramified morphology, but has no effect on TLR4-mediated inflammatory responses.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Valproic acid treatment of primary adult human microglia reduces phagocytic capacity and expression of PU.1 and CD45.

    “Valproic acid treatment, which selectively inhibits the catalytic activity of class I HDACs and induces proteasomal degradation of HDAC2, of primary adult human microglia reduces phagocytic capacity and expression of PU.1 and CD45, suggesting the its regulation of microglial phagocytosis via epigenetic mechanism [36-38].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [36] Krämer OH,, The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. The EMBO journal, 2003 22(13): p. 3411– 3420. 12840003 PMC165640 source

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    Interpretationcitation

    PU.1 is necessary for microglial development and functional maintenance.

    “suggesting the necessity of PU.1 for microglial development and functional maintenance [1].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Kierdorf K,, Microglia emerge from erythromyeloid precursors via Pu.1- and irf8-dependent pathways. Nature Neuroscience, 2013 16: p. 273. 23334579 source

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    Premisecitation

    Inhibition of histone deacetylase increases H4 acetylation and disrupts interaction between the PU.1 locus and RNA polymerase II, suppressing PU.1 transcription in murine microglia.

    “Inhibition of histone deacetylase (HDAC) increases acetylation of H4 and disrupts the interaction between the locus and RNA polymerase II, leading to the suppression of PU.1 transcription in murine microglia [35, 36].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Laribee RN and Klemsz MJ, Histone H4 HDAC activity is necessary for expression of the PU.1 gene. Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression, 2005 1730(3): p. 226– 234. 16139904 source

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    • cites [36] Krämer OH,, The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. The EMBO journal, 2003 22(13): p. 3411– 3420. 12840003 PMC165640 source

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    Interpretationcitation

    Studies with HDAC inhibitors show that the microglial transcriptome can be epigenetically regulated, possibly through PU.1 suppression.

    “Studies with HDAC inhibitors show that microglial transcriptome can be epigenetically regulated, possibly through PU.1 suppression.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Genetic ablation of miR-155 can reverse abnormal microglia signature and ameliorate disease in SOD1 ALS mice.

    “which if genetically ablated, can reverse abnormal microglia signature and ameliorate disease in SOD1 mice, a mouse model for ALS [12, 45].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Hickman SE,, The microglial sensome revealed by direct RNA sequencing. Nat Neurosci, 2013 16(12): p. 1896– 905. 24162652 PMC3840123 source

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    Premisecitation

    Peripheral immune stimulation and cerebral beta-amyloidosis can lead to epigenetic modification in microglia.

    “Peripheral immune stimulation and cerebral beta-amyloidosis can lead to epigenetic modification in microglia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Wendeln A-C,, Innate immune memory in the brain shapes neurological disease hallmarks. Nature, 2018 556(7701): p. 332– 338. 29643512 PMC6038912 source

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    Premisecitation

    Microglia can efficiently clear apoptotic cells and debris, and this is regulated by H3K27me3.

    “Microglia can efficiently clear apoptotic cells and debris, which is regulated by H3K27me3, a histone methylation occurring on the amino (N) terminal tail of the core histone H3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    In contrast to striatum microglia, cerebellar microglia displayed a phagocytic phenotype with reduced ramifications and cell volume characteristic of immature microglia and MGnD, but lacked enrichment of pro-inflammatory genes in mice.

    “In contrast to striatum microglia (stMG), cerebellar microglia (cbMg) displayed a phagocytic microglia phenotype with reduced ramifications and cell volume that is characteristic of immature microglia and MGnD, but lack enrichment of pro-inflammatory genes in mice [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Ayata P,, Epigenetic regulation of brain region-specific microglia clearance activity. Nature Neuroscience, 2018 21(8): p. 1049– 1060. 30038282 PMC6090564 source

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    Premisecitation

    The gut microbiome has emerged as a key regulator of the immune system and microglial physiology.

    “The gut microbiome has emerged as a key regulator of the immune system and microglial physiology.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Erny D,, Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci, 2015 18(7): p. 965– 977. 26030851 PMC5528863 source

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    Premisecitation

    Microglia from polyI:C offspring have reduced expression of PU.1 and its target genes, and minocycline restores this expression.

    “Microglia from polyI:C offspring had reduced expression of PU.1 and its target genes, which were restored after administration of anti-inflammatory drug minocycline [26, 59].”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Interpretationcitation

    Gut microbiota can induce subtle but global chromatin accessibility changes during embryonic microglia development and regulate key targets involved in microglial maturation in sex- and stage-specific ways.

    “These studies suggest that gut microbiota can induce subtle, but global chromatin accessibility changes during embryonic microglia development and regulates several key targets involved in microglial maturation in sex and stage-specific manner.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Their results demonstrated upregulation of CD33, INPP5D, MS4A4A, SORL1, and TREM2 in aged microglia, but no change in PU.1.

    “Their results demonstrated upregulation of CD33, INPP5D, MS4A4A, SORL1, and TREM2 in aged microglia, but no change in PU.1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Olah M,, A transcriptomic atlas of aged human microglia. Nat Commun, 2018 9(1): p. 539. 29416036 PMC5803269 source

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  • May combine two claims.

    Interpretationreasoning

    Aged microglia show reduced sensome gene expression and increased neuroprotection gene expression.

    “In summary, aged microglia show reduced expression of sensome genes and increased expression of neuroprotection genes, which are modulated by RUNX1, IRF8, PU.1 and TAL1, supporting aged microglia should be not considered dysfunctional but rather have shifting functional roles in aged brain to maintain brain circuit function.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Germ-free conditions lead to impaired microglial maturation, differentiation, and function.

    “while germ-free (GF) condition led to impaired microglia maturation, differentiation and function [15].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Erny D,, Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci, 2015 18(7): p. 965– 977. 26030851 PMC5528863 source

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    Interpretationcitation

    This suggests a reactive state and reduced plasticity in adult microglia, possibly due to repeated infections and debris clearance.

    “suggesting their reactive state and reduced plasticity in the adult stage possibly due to repetitive exposure to infectious agents and active removal of cell debris [53, 55].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [53] Wehrspaun CC, Haerty W, and Ponting CP, Microglia recapitulate a hematopoietic master regulator network in the aging human frontal cortex. Neurobiology of Aging, 2015 36(8): p. 2443.e9– 2443.e20. PMC4503803 26002684 source

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    Premisecitation

    Olah et al. suggested a protective effect of the APOE2 haplotype against increased expression of the aged human microglia gene set in human microglia.

    “More recently, Olah et al. suggested a protective effect of APOE2 haplotype against increased expression of aged human microglia gene set in human microglia [12, 56].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Hickman SE,, The microglial sensome revealed by direct RNA sequencing. Nat Neurosci, 2013 16(12): p. 1896– 905. 24162652 PMC3840123 source

      Not checked in the free run.

    • cites [56] Olah M,, A transcriptomic atlas of aged human microglia. Nat Commun, 2018 9(1): p. 539. 29416036 PMC5803269 source

      Not checked in the free run.

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    Premisecitation

    Microglia in C57BL/6J SPF and GF mice acquire sexually dimorphic transcriptome profiles and respond differently to the GF environment.

    “More recently, Thion et al. demonstrated that microglia acquire sexually dimorphic transcriptome profiles and different response to the GF environment in C57BL/6J SPF and GF mice [57].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Thion MS,, Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner. Cell, 2018 172(3): p. 500– 516.e16. 29275859 PMC5786503 source

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  • May combine two claims.

    Interpretationreasoning

    PU.1 and other transcription factors are critical in maintaining the homeostatic microglia transcriptome, but can be influenced by neurodegenerative disorder or TBI.

    “Together, these studies imply that PU.1 and other transcription factors are critical in maintaining homeostatic microglia transcriptome, but can be influenced by neurodegenerative disorder or TBI.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    PU.1 is a critical regulator of microglial identity and survival and can be regulated by microbiota independently of sex.

    “However, PU.1 was not among the top transcription regulators, supporting the idea that PU.1 is a critical regulator in microglial identity and survival that can be regulated by the presence of microbiota in sex-independent manner.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Immune training and induction of immune memory in microglia may help suppress their pro-inflammatory response in disease states.

    “Immune training and induction of immune memory of microglia can be potentially beneficial in suppressing their pro-inflammatory response in disease states.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    RNA-seq and ChIP-seq are powerful for characterizing microglia in homeostatic and neurodegenerative states but have certain limitations.

    “RNA-seq and ChiP-seq provide powerful platforms to characterize microglia in homeostatic and neurodegenerative state, but face certain limitations (Table 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Single-cell RNA and ChIP sequencing can characterize subpopulations and distinct transcriptomic phenotypes but may be limited by sequencing depth.

    “Single-cell RNA and ChiP-sequencing can provide characterization of subpopulations, distinct transcriptomic phenotype, but may have significant limitation in sequencing depth.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Adding key maintenance factors can hinder interpretation of in vitro disease models because factors such as CSF1 promote microglia viability and increase PU.1 expression, which can affect microglial function in disease.

    “However, the addition of key factors for microglial maintenance can hinder the interpretation of In vitro disease models, since factors such as CSF1 can promote microglia viability and increased PU.1 expression that can also influence microglial function in disease states [76].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Smith AM,, M-CSF increases proliferation and phagocytosis while modulating receptor and transcription factor expression in adult human microglia. Journal of Neuroinflammation, 2013 10(1): p. 859. PMC3729740 23866312 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early life stress from maternal separation can induce a pro-inflammatory microglia phenotype in offspring and reduce PU.1 transcriptional activity.

    “Early life stress caused by maternal separation can induce pro-inflammatory microglia phenotype in offspring and reduced PU.1 transcriptional activity [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Delpech J-C,, Early life stress perturbs the maturation of microglia in the developing hippocampus. Brain, behavior, and immunity, 2016 57: p. 79– 93. PMC5010940 27301858 source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    The downregulated genes in polyI:C offspring microglia include Fcgr1, Itgav, P2ry6, Sirpa, Siglece, and Cx3cr1, which constitute the sensome.

    “Downregulated genes included Fcgr1, Itgav, P2ry6, Sirpa, Siglece and Cx3cr1 that constitute the sensome.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Maternal immune activation has a significant environmental effect on the microglial gene expression phenotype, which is regulated by PU.1 and resembles microglia from AD mouse models including APP/PS1 mice.

    “This study demonstrates the significant environmental effect by maternal immune activation on microglial gene expression phenotype, which are regulated by PU.1, and show similarity to those of microglia derived from AD mouse models including APP/PS1 mice (Table 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    PU.1 can interact with other specific transcription factors and epigenetic regulators such as HDAC, underscoring its importance in controlling microglial homeostatic and reactive states at transcriptional and epigenetic levels.

    “Current studies show that PU.1 can interact with the other specific transcription factors and epigenetic regulators such as HDAC, highlighting the importance of PU.1 in regulating microglial homeostatic and reactive state at transcriptional and epigenetic levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Most transcript levels are similar between human and mouse microglia, but some genes show species-specific bias in expression magnitudes.

    “Gosselin et al. reported that majority of transcript levels between human and mouse microglia were similar, but there are genes with species-specific bias in expression magnitudes [22].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Gosselin D,, An environment-dependent transcriptional network specifies human microglia identity. Science, 2017 356(6344). PMC5858585 28546318

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oral treatment of polyI:C offspring with human commensal Bacteroides fragilis alters gut microbiota composition and ameliorates MIA phenotypes including behavioral abnormalities.

    “In addition, when polyI:C offspring are orally treated with human commensal Bacteroides fragilis, the gut microbiota composition is altered and ameliorates MIA phenotypes including behavioral abnormalities [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Hsiao EY,, Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell, 2013 155(7): p. 1451– 63. 24315484 PMC3897394 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    PU.1 is among the more specific factors critical for microglial identity and survival and responds to microenvironmental cues.

    “Among these factors, PU.1 is one of the more specific factors critical to microglial identity and survival and is sensitive to micro-environmental cues.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The gut microbiota strongly influence host metabolism and behavior, as seen in studies of microglial development and maternal immune activation.

    “Together, these studies suggest microbiota have a large impact on the host metabolome and behavior as observed in microglia development and MIA studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Gosselin D,, Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell, 2014 159(6): p. 1327– 1340. 25480297 PMC4364385 source

      Not checked in the free run.

    • cites [22] Gosselin D,, An environment-dependent transcriptional network specifies human microglia identity. Science, 2017 356(6344). PMC5858585 28546318

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Primary human microglia are still poorly characterized because they are hard to access and lack standardized isolation and culture methods.

    “Primary human microglia remain poorly characterized due to limited accessibility, lack of standardized isolation methods and culturing conditions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Many microglia culture protocols need complex recipes that induce key microglial regulators including PU.1 to mimic microglia in vivo.

    “Numerous protocol used to culture microglia require complex recipes that induces key microglial regulators including PU.1 to recapitulate microglia in vivo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Human microglia express higher levels of complement genes C2 and C3 and developmental genes SYNDIG1 and GLDN than mouse microglia, revealing distinct transcriptome differences.

    “Expression levels for complement system genes such as C2 and C3 and brain structure developmental genes including SYNDIG1 and GLDN were higher in human microglia, showing distinct differences between the human and microglia transcriptome [22].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Gosselin D,, An environment-dependent transcriptional network specifies human microglia identity. Science, 2017 356(6344). PMC5858585 28546318

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cultured microglia develop an immature phenotype with amoeboid shape, rapid proliferation, and increased phagocytic activity.

    “Another limitation of microglia culture is that it develops immature microglia with amoeboid morphology, rapid proliferation, and heightened phagocytic activity [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Kettenmann H,, Physiology of microglia. Physiol Rev, 2011 91. 21527731 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dysregulation of transcription factors in disease likely changes the microglial gene expression landscape and may contribute to disease progression.

    “Dysregulation of transcription factors in disease states are likely responsible for altering the microglial gene expression landscape, which may contribute to the disease progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    When co-cultured with iPSC-derived neurons, iMG are more motile and secrete fewer cytokines than in monoculture.

    “When co-cultured with iPSC-derived neurons, iMG display a more motile phenotype and dampened secretion of cytokines compared to monoculture [67, 68].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] Muffat J,, Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med, 2016 22(11): p. 1358– 1367. 27668937 PMC5101156 source

      Not checked in the free run.

    • cites [68] Abud EM,, iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron, 2017 94(2): p. 278– 293 e9. 28426964 PMC5482419 source

      Not checked in the free run.

54 of 54

  • The paper relies on this without support.

    Microglia are resident immune cells that maintain homeostasis in the central nervous system.

    “Microglia are the resident immune cells that maintain homeostasis in the central nervous system (CNS).”

  • The paper relies on this without support.

    Microglia and BAMs both express CD11b and low CD45, making them hard to distinguish without localization patterns.

    “Both microglia and BAMs are CD11b+/CD45low, making it difficult to distinguish between them without localization patterns.”

  • The paper relies on this without support.

    The human microbiota is more complex than laboratory mouse microbiota because of changing diet and activities.

    “The human microbiota can be more complex due to changing diet and activities compared to laboratory mice microbiota.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • PU.1 belongs to the ETS family of transcription factors and is central to myeloid lineage specification, including the development and functional identity of macrophages and microglia.

    “PU.1 belongs to the ETS family of transcription factors and is central to myeloid lineage specification, including the development and functional identity of macrophages and microglia.”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [27]

    The ‘Elucidating critical transcriptional regulators’ section identifies PU.1 as an ETS-domain transcription factor involved in immune-cell and microglial development. ‘The role of PU.1 in the maintenance of homeostatic microglia’ calls it a master regulator of microglial development and function. The copy does not establish the claim about macrophage development and functional identity specifically; page numbers were not available. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • SPI1 is a regulatory node capable of shaping many downstream immune, phagocytic, lipid-handling, and inflammatory pathways at once.

    “This means that SPI1 is not simply another Alzheimer ’s-associated gene; it is a regulatory node capable of shaping many downstream immune, phagocytic, lipid-handling, and inflammatory pathways at once.”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [27]

    In “The role of PU.1 in the maintenance of homeostatic microglia” (page unavailable), the paper identifies SPI1-encoded PU.1 as a master regulator of microglial functions, including phagocytosis and antigen presentation, and suggests a role in pro-inflammatory responses. It does not establish a PU.1-regulated lipid-handling pathway, and it explicitly says PU.1 has no effect on TLR4-mediated inflammatory responses. The broad regulatory-node characterization is supported, but the full list of pathways is not. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Many of these transcription factors were well documented.

    “many of which were well documented61–66.”

    From A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain (2023) · cites this paper as [65]

  • SPI1, encoding PU.1, is a key determinant of microglial identity and disease responsiveness.

    “Among the regulatory nodes controlling these states, SPI1, which encodes the myeloid transcription factor PU.1, has emerged as a key determinant of microglial identity and disease responsiveness.”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [27]

  • In the brain, PU.1 helps organize the enhancer landscape that allows microglia to maintain their identity, respond to environmental signals, and activate disease-relevant gene programs.

    “In the brain, PU.1 helps organize the enhancer landscape that allows microglia to maintain their identity, respond to environmental signals, and activate disease-relevant gene programs.”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [27]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Hsiao, 2013, The microbiota modulates gut physiology and behavioral abnormalities associated with autism, Cell, 155, 1451, 10.1016/j.cell.2013.11.024 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Yeh, H., & Ikezu, T.
Affiliations
Boston University (US)
Corresponding author
  • Yeh, Hana
  • Ikezu, Tsuneya
ORCID
Venue
Trends in Molecular Medicine
Publisher
Elsevier BV
Published
2019-02
Volume
25
Issue
2
Pages
96-111
ISSN
1471-4914 (ISSN-L)
DOI
10.1016/j.molmed.2018.11.004
PMC
PMC6377292
OpenAlex
W2905139641
Semantic Scholar
72a106b54b33aa89a4067b1915716f1a5436bbb3
Cited by
135
References
89
Citations by year
2026: 22 · 2025: 23 · 2024: 15 · 2023: 24 · 2022: 21 · 2021: 17 · 2020: 10 · 2019: 3
FWCI
0.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Molecular Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Foundation for the National Institutes of Health (1RF1AG05419, 5T32GM008541)
  • Nancy Lurie Marks Family Foundation
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
microglia, transcriptional regulation, epigenetic regulation, PU.1, microglial development, microglial activation, neurodegenerative diseases, microbiota, early life stress, maternal immune activation, innate immune response, brain homeostasis, transcription factors
MeSH terms
Proto-Oncogene Protein Spi-1, Animals, Humans, Nervous System Diseases, Proto-Oncogene Proteins, Transcriptional Activation, Trans-Activators, Microglia, Epigenesis, Genetic, Gene Regulatory Networks, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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