Transcription factors that define the epigenome structures and transcriptomes in microglia
Open accessAbstract
Microglia, the resident macrophages of the brain, play critical roles in maintaining brain health. Recent genome-wide analyses, including ATAC-seq, ChIP-seq/CUT&RUN, and single-cell RNA-seq, have identified key transcription factors that define the transcriptome programs of microglia. Four transcription factors-PU.1, Irf8, Sall1, and Smad4-form enhancer complexes and act as lineage-determining factors, shaping microglial identity. These factors co-bind with other lineage-determining transcription factors, directing one toward designated regions that program microglia while inhibiting the other from binding to DNA. Other transcription factors, such as Batf3 and Mafb, contribute to transcriptional cascades in microglia. TGF-β is a crucial cytokine driving these transcription factors to bind DNA and maintain homeostatic microglia. These findings provide insights into the physiological aspects of microglia and their roles in neuroinflammatory and neurodegenerative diseases.
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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 [26]
The PU.1 section (page unavailable) identifies Spi1 as encoding PU.1 and describes PU.1 as essential to microglia and involved in enhancers that regulate cellular identity. It also describes a disease-associated-like phenotype after deletion of an enhancer bound by several factors, but does not establish PU.1 itself as a key determinant of disease responsiveness. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSPI1 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 [26]
The PU.1 section (page unavailable) identifies PU.1 as encoded by SPI1 and describes it as a transcriptional activator upstream of IRF8, supporting its role as a regulatory node. The copy does not establish that SPI1 shapes all four specified downstream pathways—particularly lipid-handling and phagocytic pathways—at once. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn 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 [26]
The PU.1 section (page unavailable) describes PU.1 as a component of microglial super-enhancers and says its enhancer-promoter interactions occur at genes that define microglia, supporting the identity claim. It does not establish that PU.1 enables responses to environmental signals or activates disease-relevant gene programs. Instead, the Conclusions assign responses to external cues to SMAD4, while the PU.1 section reports DAM-like gene expression after deletion of a super-enhancer. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPU.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 [26]
The PU.1 section identifies PU.1 as an Ets-family transcription factor and describes its role in hematopoietic cell fate and microglial identity. “A stepwise development of microglia” also says microglial progenitors emerge through PU.1-dependent pathways. Our copy does not establish the same developmental and functional-identity role for macrophages generally. (LLM, conf=0.83)
Experimental — accuracy not yet measured
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The molecular determinants of microglial developmental dynamics
Barry-Carroll, L., & Gómez‐Nicola, D. (2024) · Nature reviews. Neuroscience · doi:10.1038/s41583-024-00813-1 · Cited by 45 · see citing works
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Transcriptional regulation of DC fate specification
Bosteels, C., & Scott, C. L. (2020) · Molecular Immunology · doi:10.1016/j.molimm.2020.02.021 · Cited by 41 · see citing works
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Ikzf1 as a novel regulator of microglial homeostasis in inflammation and neurodegeneration
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Microglia pack a toolbox for life
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Induced cell-autonomous neutropenia systemically perturbs hematopoiesis in Cebpa enhancer-null mice
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Self-citationBRD4 expression in microglia supports recruitment of T cells into the CNS and exacerbates EAEPreprint
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Flagged first, then by citations
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Cited by
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The Double Face of Microglia in the Brain
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lncRNA Glelr modulates microglia inflammatory programs in association with PU.1
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“Reviews of microglial transcriptional regulation have therefore placed PU.1 alongside factors such as IRF8, SALL1, SMAD proteins, and other enhancer-associated regulators that define microglial identity and reactivity [26,27].”
IRF8 deficiency causes anxiety-like behavior in a sex-dependent mannerPreprint
Zhu, S., Saeki, K., Karlsson, R., Abebe, D. T., & Ozato, K. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.02.673764
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MAF transcription factors: Emerging key players in cardiovascular health and disease
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IRF8 deficiency causes anxiety-like behavior with sex differences
Zhu, S., Saeki, K., Yamada, L., Karlsson, R., Abebe, D., & Ozato, K. (2026) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2026.101395
Self-citationLiang, J., Cao, H., 任秀敏, Sha, N., Han, X., Jiang, L., Liu, B., & Zhao, W. (2026) · Aging Cell · doi:10.1111/acel.70785
- Authors
- Saeki, K., & Ozato, K.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Saeki, Keita
- Ozato, Keiko
- Venue
- Experimental Hematology
- Publisher
- Elsevier BV
- Published
- 2025-09
- Volume
- 149
- Pages
- 104814
- ISSN
- 0301-472X (ISSN-L)
- PMC
- PMC12229243
- OpenAlex
- W4410717078
- Cited by
- 11
- References
- 92
- Citations by year
- 2026: 9 · 2025: 2
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- Locations
- Experimental Hematology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- Kumamoto University
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- microglia, transcription factors, microglial transcriptome, epigenome, PU.1, IRF8, SALL1, SMAD4, Batf3, MAFB, lineage determination, TGF-beta signaling, neuroinflammation, neurodegenerative diseases, transcriptional cascade
- MeSH terms
- Epigenome, Animals, Humans, Transcription Factors, Transforming Growth Factor beta, Microglia, Neurodegenerative Diseases, Transcriptome
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