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Cited by 74Neuroinflammation and Neurodegeneration MechanismsGenomics and Chromatin DynamicsMultiple Sclerosis Research Studies

A comprehensive profile of ChIP-Seq-based PU.1/Spi1 target genes in microglia.

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Satoh, Jun-ichi, Asahina, Naohiro, Kitano, Shouta, Kino, Yoshihiro·2014·Gene Regulation and Systems Biology
DOI 10.4137/grsb.s19711PMC PMC4262374
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Abstract

Microglia are resident mononuclear phagocytes that play a principal role in the maintenance of normal tissue homeostasis in the central nervous system (CNS). Microglia, rapidly activated in response to proinflammatory stimuli, are accumulated in brain lesions of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. The E26 transformation-specific (ETS) family transcription factor PU.1/Spi1 acts as a master regulator of myeloid and lymphoid development. PU.1-deficient mice show a complete loss of microglia, indicating that PU.1 plays a pivotal role in microgliogenesis. However, the comprehensive profile of PU.1/Spi1 target genes in microglia remains unknown. By analyzing a chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) dataset numbered SRP036026 with the Strand NGS program, we identified 5,264 Spi1 target protein-coding genes in BV2 mouse microglial cells. They included Spi1, Irf8, Runx1, Csf1r, Csf1, Il34, Aif1 ( Iba1), Cx3cr1, Trem2, and Tyrobp. By motif analysis, we found that the PU-box consensus sequences were accumulated in the genomic regions surrounding ChIP-Seq peaks. By using pathway analysis tools of bioinformatics, we found that ChIP-Seq-based Spi1 target genes show a significant relationship with diverse pathways essential for normal function of monocytes/macrophages, such as endocytosis, Fc receptor-mediated phagocytosis, and lysosomal degradation. These results suggest that PU.1/Spi1 plays a crucial role in regulation of the genes relevant to specialized functions of microglia. Therefore, aberrant regulation of PU.1 target genes might contribute to the development of neurodegenerative diseases with accumulation of activated microglia.

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  • Seven genes (Syk, Lyn, Stat1, Entpd1, Rgs10, Fcgr1, and Fcgr3) are directly targeted by Spi1 and may be involved in phagocytosis.

    “Based on the “Immune response_Phagocytosis” components and the Spi1 chromatin immunoprecipitation sequencing (ChIP-Seq) data38,39, we selected seven genes (Syk, Lyn, Stat1, Entpd1, Rgs10, Fcgr1, and Fcgr3) that are directly targeted by Spi1 and may be involved in phagocytosis.”

    From Deletion of SPI1 in microglia exacerbates amyloid pathology by impairing microglial response in Alzheimer’s disease models (2026) · cites this paper as [39]

    The Results section on target-gene identification names Syk as a ChIP-Seq-based Spi1 target, and the molecular-networks Results section links the broader target set to phagocytosis pathways (page numbers unavailable). Our copy does not identify Lyn, Stat1, Entpd1, Rgs10, Fcgr1, or Fcgr3 as Spi1 targets or link each of the seven genes to phagocytosis. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • SPI1/PU.1 is a master regulator of microglial development and homeostasis and of several Alzheimer's disease genetic risk genes, and small changes in PU.1 expression can significantly affect cell function.

    “SPI1/PU.1 is a master regulator of microglial development and homeostasis and the expression of several AD genetic risk genes, e.g. ABCA7, CD33, MS4A4A, MS4A6A, TREM2, APOE and CLU, and small changes in PU.1 expression can significantly affect cell function (Huang et al., 2017; Satoh et al., 2014).”

    From Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response (2021) · cites this paper as Satoh et al., 2014

    The Introduction and Discussion (pages unavailable) support PU.1’s importance for microglial development and function: PU.1-deficient mice lack microglia, and PU.1 knockdown reduces human microglial viability and phagocytosis. The paper identifies Trem2 as a Spi1 target, but does not establish regulation of the other listed Alzheimer’s disease risk genes or show that small changes in PU.1 expression significantly affect cell function. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • PU.1 influences immune responses by regulating the expression of Aif1, Cx3cr1, Trem2, and Tyrobp.

    “In addition, PU.1 influences immune responses by regulating the expression of allograft inflammatory factor 1 (Aif1, also known as ionized calcium‐binding adapter molecule 1, Iba1), C‐X3‐C motif chemokine receptor 1 (Cx3cr1), triggering receptor expressed on myeloid cells 2 (Trem2), and TYRO protein tyrosine kinase binding protein (Tyrobp) [32, 36].”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [32]

    The Results (page not specified) identify Aif1, Cx3cr1, Trem2, and Tyrobp as ChIP-Seq-based Spi1 targets in mouse microglial cells. The Discussion cautions that ChIP-Seq binding does not always correspond to biological activity. The paper therefore supports their identification as potential targets, but does not establish that PU.1 regulates expression of all four genes to influence immune responses. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • PU.1 induces the transcription of several surface receptors, such as ITGAM, VCAM1, TREM2, and TYROBP, thereby enhancing microglial phagocytic capacity for Aβ clearance.

    “As shown in Figure 1, previous studies showed that PU.1 induces the transcription of several surface receptors, such as Integrin subunit alpha M (ITGAM, also known as CD11b), vascular cell adhesion molecule 1 (VCAM1, also known as CD106), TREM2, and TYROBP [32, 55], thereby enhancing microglial phagocytic capacity for Aβ clearance [56, 57].”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [32]

    The Results (Identification of 5,264 ChIP-Seq-based Spi1 target genes in mouse microglia; page unavailable) identify Trem2 and Tyrobp as Spi1 targets. The retrieved passages do not identify ITGAM or VCAM1 as targets, and identifying ChIP-Seq targets does not itself demonstrate that PU.1 induces their transcription. The Aβ-clearance clause is attached to different citations in the citing sentence. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • PU.1, IRF8, and BHLHE40/41 regulate multiple downstream targets that orchestrate microglial immune response functions, including phagocytosis, cytokine production, and inflammatory signaling.

    “PU.1, IRF8, and BHLHE40/41 regulates multiple downstream targets that orchestrate microglial immune response functions, including phagocytosis, cytokine production, and inflammatory signaling”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [32]

    The Results (pages not specified in our copy) identify numerous PU.1/Spi1 targets in mouse microglial cells, including Irf8, and link those targets to phagocytosis and signaling pathways. The Introduction also describes reduced phagocytic activity in IRF8-deficient microglia. The paper does not establish that IRF8 or BHLHE40/41 regulate the downstream targets responsible for the listed functions, nor does it link those factors to cytokine production. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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References 46 · Cited by 74

Research works printed but not linked: 34

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Authors
Satoh, J.-I., Asahina, N., Kitano, S., & Kino, Y.
Affiliations
Meiji Pharmaceutical University (JP)
Corresponding author
Satoh, Jun-ichi
ORCID
Kino, Yoshihiro
Venue
Gene Regulation and Systems Biology
Publisher
SAGE Publications
Published
2014-01
Volume
8
Pages
127-39
ISSN
1177-6250 (ISSN-L)
DOI
10.4137/grsb.s19711
PMC
PMC4262374
OpenAlex
W1974504285
Cited by
74
References
46
Citations by year
2026: 4 · 2025: 8 · 2024: 4 · 2023: 5 · 2022: 8 · 2021: 9 · 2020: 9 · 2019: 3 · 2018: 9 · 2017: 9 · 2016: 3 · 2015: 3
FWCI
2.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Gene Regulation and Systems Biology (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Japan Society for the Promotion of Science (25430054)
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 factor target genes, BV-2 cells, IRF8, CSF-1, CX3CR1, TREM2, phagocytosis, lysosomal degradation, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, myeloid development

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