Affinage

Showing SPI1 — SPI-1 is a alias.

SPI1

Transcription factor PU.1 · UniProt P17947

Length
270 aa
Mass
31.1 kDa
Annotated
2026-06-10
100 papers in source corpus 46 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPI1/PU.1 is an ETS-family transcription factor that acts as the master regulator of hematopoietic lineage commitment, where its dose dictates cell fate and its loss abolishes development of B cells, macrophages, and functionally competent neutrophils (PMID:8896458, PMID:9716585, PMID:15657291). PU.1 operates as a chromatin pioneer: cryo-EM and crystallographic structures show it engages nucleosomal DNA at the exit linker, shifting ~17 bp into the core through contacts with histone H2A to unwrap ~20 bp and, together with C/EBPα, displace linker histone H1 to open condensed chromatin (PMID:38267599). Although PU.1 cannot fully access nucleosomal sites in isolation in vitro, its N-terminal acidic activation domain recruits SWI/SNF remodeling complexes to drive de novo chromatin access and redistribute partner transcription factors in vivo (PMID:31964861, PMID:30171019). It functions combinatorially through composite ETS-IRF elements with IRF4 and IRF8 — interactions defined structurally and biochemically — programming distinct B-cell, microglial, and inflammasome gene sets (PMID:12453417, PMID:9642085, PMID:25288399, PMID:30484118). Beyond activation, PU.1 enforces lineage repression: it recruits HDAC1 to deacetylate bound enhancers (reinforced by PRC2-deposited H3K27me3) to silence erythroid and innate-immune programs, and partners with pRB to block GATA-1-driven erythroid differentiation (PMID:14559995, PMID:30911105, PMID:35871293). PU.1 transactivates cytokine-receptor genes including c-fms and IL-7Rα to license lineage-specific cytokine responsiveness, and it is itself controlled by a regulatory architecture spanning TNF-induced induction in HSCs, GATA-1/GATA-2 repression of its locus, Runx1 action at its upstream regulatory element, and cell-cycle-coupled positive autoregulation (PMID:9687512, PMID:11869689, PMID:19491391, PMID:23868921, PMID:30301719, PMID:31431533). PU.1 acts as a hematopoietic euchromatin gatekeeper whose haploinsufficiency causes agammaglobulinemia in humans, and hypomorphic PU.1 cooperates with mismatch-repair or Tet2 deficiency to drive AML, a context in which minor-groove-binding diamidines that allosterically disrupt PU.1-chromatin contacts show therapeutic activity (PMID:29083320, PMID:33951726, PMID:35820129). PU.1 additionally drives pro-fibrotic fibroblast programs, and its pharmacological inactivation reverses fibrosis (PMID:30700907).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1988 High

    Established the locus as a candidate oncogene by linking its activation to virally induced leukemia, motivating all subsequent functional study.

    Evidence Retroviral integration site and expression analysis across murine erythroleukemia tumors

    PMID:2827041

    Open questions at the time
    • Did not define the protein's molecular activity
    • No mechanism linking overexpression to transformation
  2. 1996 High

    Resolved whether PU.1 is required for hematopoietic development by showing its DNA-binding function is essential for B cell and macrophage differentiation while sparing erythroid/megakaryocytic lineages.

    Evidence Targeted disruption of the PU.1 DNA-binding domain in mice with histology and flow cytometry

    PMID:8896458

    Open questions at the time
    • Direct target genes not identified
    • Did not separate lineage-specification from terminal-differentiation roles
  3. 1998 High

    Defined how PU.1 enables lineage-specific cytokine responsiveness by showing it is required for transcription of the M-CSF receptor c-fms, and separated receptor expression from differentiation.

    Evidence PU.1-null progenitors with retroviral c-fms rescue and cytokine assays; parallel functional analysis of null neutrophils

    PMID:9687512 PMID:9716585

    Open questions at the time
    • Receptor rescue did not restore differentiation, leaving differentiation targets undefined
  4. 1998 High

    Provided biochemical/structural basis for combinatorial control by demonstrating spacing-dependent cooperative DNA binding between PU.1 and IRF-4 through their DNA-binding domains.

    Evidence Fluorescence polarization, NMR, and domain-deletion analysis at the lambdaB element; in vivo Co-IP with TLS/FUS as an additional interactor

    PMID:9478924 PMID:9642085

    Open questions at the time
    • Atomic structure of the cooperative complex not yet resolved
    • TLS/FUS interaction was Medium-confidence single-lab
  5. 2002 High

    Delivered the atomic basis for PU.1/IRF cooperativity, explaining how composite elements select cooperative versus anticooperative pairings, and extended PU.1's reach into lymphoid cytokine signaling via IL-7Rα.

    Evidence X-ray structure of PU.1/IRF-4/DNA ternary complex; promoter analysis and retroviral IL-7Rα rescue in null progenitors

    PMID:11869689 PMID:12453417

    Open questions at the time
    • Structure used isolated DNA-binding domains, not full-length factors
    • Did not address nucleosomal context
  6. 2003 High

    Showed PU.1 acts as a repressor of competing lineages by binding GATA-1 and recruiting pRB to block erythroid differentiation, establishing antagonistic cross-regulation of fate.

    Evidence Co-IP, domain mutagenesis, ChIP, and differentiation assays in MEL cells

    PMID:14559995

    Open questions at the time
    • Genome-wide scope of PU.1-pRB co-occupancy not defined
    • In vivo relevance not tested
  7. 2005 High

    Identified post-translational and dose-based tuning of PU.1 output: p300 acetylation of specific lysines modulates transactivation, and PU.1 down-regulation marks the earliest molecular step restricting CMPs to erythroid/megakaryocytic fate.

    Evidence In vitro acetylation, mutagenesis, ChIP and reporter assays; PU.1-GFP reporter knock-in mice with in vivo reconstitution

    PMID:15657291 PMID:16210620

    Open questions at the time
    • Acetyltransferase/deacetylase balance in vivo not mapped
    • Upstream signals setting PU.1 dose not yet identified
  8. 2008 High

    Demonstrated PU.1's instructive sufficiency by showing PU.1 (with C/EBP) transdifferentiates fibroblasts into functional macrophage-like cells.

    Evidence Retroviral transcription-factor transduction into fibroblasts with phagocytosis and marker assays

    PMID:18424555

    Open questions at the time
    • Did not resolve the chromatin mechanism enabling conversion
    • C/EBP dependency not mechanistically dissected
  9. 2011 High

    Expanded PU.1's regulatory repertoire to non-coding RNA, showing it directly drives myeloid-instructive microRNAs in vivo.

    Evidence ChIP-seq, retroviral HSC overexpression with transplantation, zebrafish morpholino knockdown

    PMID:21730352

    Open questions at the time
    • Relative contribution of miRNA versus protein-coding targets to fate unclear
  10. 2013 High

    Explained how PU.1 dose is stabilized during commitment by uncovering a cell-cycle-coupled positive autoregulatory circuit.

    Evidence Quantitative live-cell imaging of a PU.1 reporter with mathematical modeling

    PMID:23868921

    Open questions at the time
    • Molecular link between cell-cycle length and PU.1 accumulation not defined
  11. 2014 High

    Mapped PU.1 locus regulation and B-lineage programming, defining CTCF/SMARCA5 recruitment to the SPI1 enhancer and the reciprocal IRF8 versus IRF4 partnerships controlling B-cell differentiation.

    Evidence Conditional B-cell knockout with expression analysis; ChIP and demethylation experiments at the SPI1 locus

    PMID:24498324 PMID:25288399

    Open questions at the time
    • CTCF/SMARCA5 result was Medium-confidence single-lab
    • Direct DNA contacts of IRF8-PU.1 at B-cell targets not structurally resolved
  12. 2015 High

    Causally linked PU.1 dose reduction to leukemogenesis, showing hypomorphic PU.1 plus MMR deficiency generates preleukemic stem cells and AML through Irf8 inhibition.

    Evidence PU.1 enhancer-deletion mouse crossed to MMR-deficient mice with transplantation and expression profiling

    PMID:26343801

    Open questions at the time
    • Did not define the full PU.1-dependent network lost during transformation
  13. 2017 High

    Provided a pharmacological strategy and senescence mechanism: minor-groove diamidines allosterically block PU.1-chromatin binding with AML activity, while PU.1 overexpression triggers DNA-binding-dependent senescence.

    Evidence Small-molecule inhibitors with ChIP and xenotransplant models; overexpression with domain mutants and senescence assays in vivo

    PMID:28912174 PMID:29083320

    Open questions at the time
    • Senescence study was Medium-confidence single-lab
    • Selectivity of diamidines for PU.1 sites genome-wide not fully resolved
  14. 2018 High

    Resolved the diamidine mechanism and clarified PU.1's upstream control and partner switching: inhibitory diamidines act through DNA minor-groove binding (not protein binding), TNF is the principal PU.1-inducing signal in HSCs, and PU.1 swaps IRF8 for NFATc1 across osteoclast differentiation.

    Evidence FP and DNA-binding competition assays; in vivo TNF perturbation with single-cell imaging; ChIP-seq across BMM-to-osteoclast transition and microglial conditional deletion

    PMID:27079976 PMID:30301719 PMID:30484118 PMID:30721543

    Open questions at the time
    • How TNF signaling is transduced to PU.1 protein stabilization not detailed
  15. 2019 High

    Established PU.1 as a repressive chromatin organizer beyond hematopoiesis: it recruits HDAC1 to restrain neutrophil enhancers and drives pro-fibrotic fibroblast programs reversible by PU.1 inactivation; Runx1 and PU.1 enforce its own URE-dependent maintenance in erythroid cells.

    Evidence Conditional Spi1 deletion with ATAC-seq/ChIP-seq and Co-IP; conditional/pharmacological PU.1 inactivation across fibrosis models; URE-deletion mouse with ChIP and ATAC-seq

    PMID:30700907 PMID:30911105 PMID:31431533

    Open questions at the time
    • Mechanism switching PU.1 between activator and repressor functions per locus unresolved
  16. 2020 High

    Reframed PU.1 pioneering: rather than directly accessing nucleosomes, PU.1 uses its acidic activation domain to recruit SWI/SNF for de novo chromatin opening and partner redistribution.

    Evidence In vitro nucleosome-binding assays plus genome-wide ChIP-seq/ATAC-seq with domain deletions; pro-T-cell perturbations defining affinity/concentration trade-offs

    PMID:30171019 PMID:31964861

    Open questions at the time
    • Structural basis of nucleosome engagement not yet shown
    • Identity of recruited remodeler subunits incompletely defined
  17. 2021 High

    Showed PU.1 functions as a human euchromatin gatekeeper and an inflammation-restraining repressor: agammaglobulinemia-causing mutations destabilize PU.1 and close euchromatin, and PU.1 represses cell-cycle/protein-synthesis genes during IL-1 stress in HSCs.

    Evidence Patient SPI1 mutations in human HSPCs with ATAC-seq and differentiation; conditional HSC knockout with IL-1 stimulation and ChIP-seq

    PMID:33857288 PMID:33951726

    Open questions at the time
    • How haploinsufficiency selectively closes specific euchromatin domains not fully mapped
  18. 2022 High

    Defined the mechanistic basis of PU.1-mediated repression and methylation-sensitive leukemogenesis: PU.1 recruits HDAC1 and synergizes with PRC2 at erythroid enhancers, while Tet2 loss plus hypomorphic PU.1 drives AML via hypermethylated PU.1 sites and failed myeloid enhancer activation.

    Evidence ChIP-seq/ATAC-seq/RNA-seq with HDAC/PRC2 inhibition in MEL cells; compound Tet2-KO/URE-deletion mouse genetics with WGBS and transplantation

    PMID:35820129 PMID:35871293

    Open questions at the time
    • Locus-specific cues directing PU.1 to repressive versus activating complexes unresolved
  19. 2024 High

    Delivered the structural mechanism of PU.1 pioneering on a native nucleosome, showing H2A-dependent DNA unwrapping cooperative with C/EBPα and H1 displacement, and rationalizing an AML mutation.

    Evidence Cryo-EM/crystal structures of PU.1-nucleosome complexes with in vitro binding assays and Q218H mutant analysis; also IL-9/PU.1 feedback loop in arthritis (Medium)

    PMID:38267599 PMID:39164066

    Open questions at the time
    • Structures captured a single enhancer context
    • In vivo coupling of unwrapping to SWI/SNF recruitment not directly visualized

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what locus-specific molecular determinants direct PU.1 between activating (SWI/SNF) and repressive (HDAC1/PRC2) chromatin programs, and how PU.1 dose, post-translational modification, and partner availability are integrated to set these choices genome-wide.
  • No unified model linking PU.1 concentration to activator-versus-repressor outcome at individual loci
  • Determinants of cofactor selection (p300 vs HDAC1 vs PRC2) per site unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 5 GO:0060090 molecular adaptor activity 3 GO:0042393 histone binding 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4
Partners
CEBPAGATA1HDAC1IRF4IRF8MITFNFATC1RB1
Complex memberships
PU.1/IRF composite-element complex (with IRF4/IRF8)PU.1/MITF osteoclast complex

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Targeted disruption of the PU.1 DNA-binding domain in mice results in absence of mature macrophages, neutrophils, B cells, and T cells, while erythrocytes and megakaryocytes are preserved, establishing PU.1 as absolutely required for normal differentiation of B cells and macrophages. Gene knockout mouse (targeted disruption of PU.1 DNA-binding domain), histological and flow cytometric analysis The EMBO journal High 8896458
1988 Spi-1/PU.1 was identified as a putative oncogene by retroviral insertional mutagenesis: SFFV proviral integration at the Spi-1 locus was found in 95% of virally induced murine erythroleukemia tumors, with concomitant induction of a 4.0 kb mRNA. Southern blot integration site analysis, Northern blot expression analysis in primary tumors Nature High 2827041
1998 PU.1-null myeloid progenitors fail to respond to M-CSF due to absence of c-fms (M-CSF receptor) gene transcription; retroviral transduction of c-fms restores M-CSF-dependent proliferation but does not induce macrophage differentiation, demonstrating that PU.1 controls myelopoiesis by regulating both cytokine receptor expression and differentiation. PU.1 knockout mouse-derived progenitors, retroviral transduction of c-fms, cytokine responsiveness assays The EMBO journal High 9687512
1998 PU.1-null neutrophils fail to terminally differentiate: they lack secondary granule components and are defective in chemokine responses, superoxide production, and bacterial killing; the absence of gp91(phox) mRNA explains the superoxide defect. PU.1 knockout mouse, flow cytometry, functional assays (superoxide, phagocytosis), RT-PCR Blood High 9716585
2002 Crystal structure of the PU.1/IRF-4/DNA ternary complex reveals that DNA adopts an unusual S-shape, juxtaposing PU.1 and IRF-4 for selective electrostatic and hydrophobic interactions across the minor groove, providing structural basis for cooperative versus anticooperative interactions between Ets and IRF factors. X-ray crystallography of ternary complex (PU.1 ETS domain + IRF-4 DBD + composite DNA element) Molecular cell High 12453417
1999 c-Jun acts as a JNK-independent coactivator of PU.1: c-Jun associates via its basic domain with the ETS domain of PU.1 (without binding DNA directly) and enhances PU.1 transactivation of the M-CSF receptor promoter; this interaction is blocked by c-Fos and is stimulated by Ras through upregulation of c-Jun expression. Co-immunoprecipitation, reporter gene assays, dominant-negative c-Jun constructs, overexpression in cell lines The Journal of biological chemistry Medium 9988737
2002 PU.1 directly regulates transcription of the IL-7Rα gene in lymphoid progenitors; retroviral transduction of IL-7Rα into PU.1-null progenitors restores IL-7-dependent proliferation and, at low frequency, generates pro-B cells. PU.1 knockout progenitors, promoter analysis, chromatin crosslinking, retroviral transduction rescue Immunity High 11869689
2003 PU.1 binds GATA-1 on DNA and recruits pRB (via an acidic N-terminal domain that interacts with pRB's C pocket) to GATA-1 target genes, repressing GATA-1 transcriptional activity and blocking erythroid differentiation; pRB co-localizes with PU.1 and GATA-1 at repressed target genes. Co-immunoprecipitation, domain-deletion mutagenesis, chromatin immunoprecipitation, reporter assays, differentiation assays in MEL cells Molecular and cellular biology High 14559995
2004 PU.1 activation drives dendritic cell fate over macrophage fate by directly binding MafB protein and inhibiting its transcriptional activity and its ability to induce macrophage differentiation; high PU.1 also suppresses MafB expression. Retroviral overexpression in myeloid progenitors and monocyte clones, protein-protein interaction assays, reporter assays Blood Medium 15598817
2005 Down-regulation of PU.1 expression in the common myeloid progenitor (CMP) is the first molecularly identified event associated with restriction of differentiation potential to the erythroid/megakaryocyte lineage. PU.1-GFP reporter knock-in mice, FACS sorting, colony-forming assays, in vivo lineage reconstitution The Journal of experimental medicine High 15657291
2007 MITF and PU.1 form complexes at osteoclast target gene promoters (cathepsin K, acid phosphatase 5) in response to CSF-1 alone; addition of RANKL further recruits p38 MAPK-phosphorylated MITF and SWI/SNF complexes to these promoters; NFATc1 is subsequently recruited during terminal differentiation. Chromatin immunoprecipitation, co-immunoprecipitation, genetic analysis in Mitf and Pu.1 mouse models, bone marrow-derived precursor differentiation assays The Journal of biological chemistry High 17403683
2008 Combination of PU.1 and C/EBPα (or C/EBPβ) transdifferentiates NIH 3T3 fibroblasts and skin fibroblasts into macrophage-like cells that phagocytose particles/bacteria, respond to CSF-1, and express myeloid surface markers; PU.1 is the primary inducer of myeloid conversion. Retroviral transduction of transcription factors into fibroblasts, flow cytometry, phagocytosis assays, gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 18424555
2009 GATA-1 and GATA-2 bind two conserved regions of the PU.1/Sfpi1 gene locus and repress its expression; GATA-1 replaces GATA-2 at the locus during erythromegakaryocytic differentiation, extinguishing PU.1 expression; GATA-2 knockdown in the absence of GATA-1 increases PU.1 expression 3-fold and reprograms cells to macrophages. ChIP, shRNA knockdown, conditional restoration of GATA-1 in Gata1-null erythromegakaryocytic progenitors, gene expression analysis Blood High 19491391
2011 PU.1 directly controls expression of at least four microRNAs (miR-146a, miR-342, miR-338, miR-155) by occupying binding sites in regulatory chromatin regions near their genomic loci; ectopic miR-146a expression directs HSC differentiation into peritoneal macrophages; disruption of Dicer or antagonization of miR-146a inhibits macrophage formation in zebrafish. ChIP-seq, miRNA expression profiling, retroviral overexpression in mouse HSCs + transplantation, morpholino knockdown in zebrafish Blood High 21730352
2013 PU.1 controls myeloid differentiation via positive feedback with the cell cycle: developing macrophages increase PU.1 levels by lengthening their cell cycles, causing stable PU.1 accumulation; exogenous PU.1 induces endogenous PU.1 accumulation by lengthening cell cycle, constituting a cell cycle-coupled positive autoregulatory circuit. Quantitative live-cell imaging of fluorescent PU.1 reporter, exogenous PU.1 expression in progenitors, mathematical modeling Science High 23868921
1998 The PU.1 PEST domain and IRF-4 residues 1–19 are unstructured in isolation; cooperation between PU.1 and IRF-4 DNA-binding domains at the lambdaB element is spacing-dependent and independent of PEST domain phosphorylation, demonstrating that protein-protein interactions through the DNA-binding domains contribute to cooperative DNA binding. Fluorescence polarization DNA-binding assays, NMR spectroscopy of 15N-labeled proteins, domain-deletion mutagenesis Journal of molecular biology High 9642085
1998 Spi-1/PU.1 interacts in vivo with TLS (FUS), an RNA-binding protein; TLS reduces PU.1's DNA-binding and transactivation abilities; Spi-1 and TLS mutually antagonize each other's effects on alternative splicing of E1A pre-mRNA. Co-immunoprecipitation in vivo, reporter transactivation assays, in vitro/in vivo splicing assays The Journal of biological chemistry Medium 9478924
2006 Spi-1/PU.1 affects alternative splice site selection in a promoter binding-dependent manner: Spi-1 must bind and transactivate a given promoter to favor use of the proximal 5' alternative splice site, indicating coupling of Spi-1's transcriptional and splicing regulatory activities. Minigene splicing reporter system, Spi-1 domain mutants, transfection in proerythroblastic cells The Journal of biological chemistry Medium 16698794
2005 PU.1 is acetylated by p300 on lysines 170, 171, 206, and 208; p300 physically interacts with PU.1 residues 7–30; mutation of K170/K171 does not affect DNA binding but lowers transcriptional activation with p300, demonstrating acetylation regulates PU.1 transactivation. In vitro acetylation assay, co-immunoprecipitation, site-directed mutagenesis, reporter assays, chromatin immunoprecipitation Journal of immunology High 16210620
2014 The IRF8-PU.1 complex promotes BCL6 and PAX5 expression and represses AID and BLIMP-1, thereby controlling B-cell class-switch recombination and plasma cell differentiation; PU.1-IRF8 functions reciprocally to IRF4. Conditional knockout mice (B-cell specific deletion), gene expression analysis, functional B-cell differentiation assays The Journal of experimental medicine High 25288399
2015 Heterozygous deletion of a PU.1 upstream regulatory enhancer (35% reduction in PU.1 expression) combined with DNA mismatch repair deficiency is sufficient to induce myeloid-biased preleukemic stem cells and their transformation to AML; AML progression involves inhibition of the PU.1-cooperating transcription factor Irf8. Enhancer deletion mouse model (hypomorphic PU.1), compound genetic crosses with MMR-deficient mice, transplantation assays, gene expression profiling Nature medicine High 26343801
2017 Small-molecule heterocyclic diamidine inhibitors allosterically interfere with PU.1-chromatin binding by interacting with the DNA minor groove flanking PU.1-binding motifs, disrupting PU.1 interaction with target gene promoters and downregulating canonical PU.1 transcriptional targets. Small-molecule inhibitor development, ChIP, reporter assays, shRNA, xenotransplantation mouse models The Journal of clinical investigation High 29083320
2016 The isosteric selenophene analog DB1976 (unlike DB270) does not bind PU.1 protein directly and strongly inhibits the PU.1/DNA complex in vitro and fully antagonizes PU.1-dependent transactivation in vivo; DB270 binds PU.1 protein independently of DNA, which abrogates its inhibitory activity. Fluorescence polarization assays, in vitro DNA-binding competition assays, cell-based reporter assays Nucleic acids research High 27079976
2019 PU.1 is an essential regulator of the pro-fibrotic gene expression program in fibroblasts; transcriptional and post-transcriptional mechanisms controlling PU.1 expression are perturbed in fibrotic diseases, upregulating PU.1 and inducing fibrosis-associated gene sets; pharmacological and genetic inactivation of PU.1 reprograms fibrotic fibroblasts into resting fibroblasts and causes regression of fibrosis in multiple organs. Conditional genetic inactivation, small-molecule PU.1 inhibitors, gene expression profiling, fibrosis models in multiple organs Nature High 30700907
2018 TNF directly and rapidly upregulates PU.1 protein in HSCs in vitro and in vivo; niche-derived TNF is the principal PU.1-inducing signal in HSCs and is both sufficient and required to relay inflammatory signals to HSCs. Live-cell imaging, in vivo cytokine administration, genetic ablation of TNF signaling in mice, quantitative single-cell protein measurement Blood High 30301719
2019 PU.1 restrains neutrophil innate immune responses by broadly inhibiting enhancer accessibility via recruitment of histone deacetylase 1 (HDAC1); this epigenetic modification prevents AP-1 transcription factor JUNB from accessing chromatin and activating its targets, constituting a PU.1-installed inhibitor program. Conditional Spi1 deletion in neutrophils, comprehensive epigenomic profiling (ATAC-seq, ChIP-seq), co-immunoprecipitation, fungal infection model Nature immunology High 30911105
2020 PU.1, in contrast to classical pioneer factors, cannot access nucleosomal target sites in vitro; ectopic PU.1 induction leads to extensive chromatin remodeling and redistribution of partner TFs in vivo; de novo chromatin access and partner TF redistribution require PU.1's N-terminal acidic activation domain and ability to recruit SWI/SNF remodeling complexes. In vitro nucleosome-binding assays, genome-wide ChIP-seq in multiple cell types with native/ectopic PU.1, ATAC-seq, domain-deletion analysis Nature communications High 31964861
2021 PU.1 is required to repress cell cycle and protein synthesis genes in HSCs during IL-1 stimulation; PU.1-deficient HSCs show aberrant protein synthesis and cell cycle activity with IL-1 exposure and undergo expansion; PU.1 directly binds repressed target genes in this context. Conditional PU.1 knockout in HSCs, IL-1 stimulation, ChIP-seq, gene expression profiling, phenotypic analysis The Journal of experimental medicine High 33857288
2021 Disease-causing heterozygous SPI1 mutations in agammaglobulinemic patients encode destabilized PU.1 proteins unable to nuclear localize or bind target DNA; in PU.1-haploinsufficient pro-B cells, euchromatin is less accessible to non-pioneer TFs critical for B cell development, defining PU.1 as a hematopoietic euchromatin gatekeeper. Patient-derived SPI1 mutations introduced into human HSPCs, in vitro B-cell and myeloid differentiation assays, ATAC-seq, subcellular localization studies The Journal of experimental medicine High 33951726
2022 SPI1/PU.1 represses genes in the erythroid lineage by binding active enhancers; HDAC1 cooperatively mediates SPI1-induced repression by deacetylating SPI1-bound enhancers, impacting promoter acetylation, chromatin accessibility, and RNA Pol II occupancy; PRC2 reinforces repression by depositing H3K27me3 at promoters; PRC2 and HDAC1 act synergistically. ChIP-seq, ATAC-seq, RNA-seq, co-immunoprecipitation, pharmacological inhibition of HDAC and PRC2 in murine erythroleukemia cells Nucleic acids research High 35871293
2018 IRF8 and PU.1 are both required for microglial activation; they directly target each other's gene transcription in a positive feedback loop; they cooperatively bind composite IRF-ETS motifs on microglial activation-related genes, and synergistic binding of IRF8 and PU.1 to composite-motif DNA was verified biochemically. Post-developmental conditional deletion in microglia, 3D fluorescence imaging, ChIP, in vitro binding assays with composite DNA motifs, gene expression analysis Protein & cell High 30484118
2019 During RANKL-induced osteoclastogenesis, PU.1 switches its transcriptional partner from IRF8 (in precursor macrophages) to NFATc1 (in osteoclasts), altering its genomic binding regions; this partner switching is associated with changes in histone modification and cell-type-specific gene expression. ChIP-seq, FAIRE-seq, genome-wide chromatin profiling in BMMs and OCs, gene expression analysis Journal of bone and mineral research High 30721543
2024 Cryo-EM/crystal structures of PU.1 bound to a nucleosome containing the CX3CR1 enhancer reveal that PU.1 binds DNA at the exit linker and shifts 17 bp of DNA into the nucleosome core via interactions with H2A, unwrapping ~20 bp; C/EBPα further unwraps ~25 bp of entry DNA aided by PU.1's repositioning; together they displace linker histone H1 and open condensed chromatin arrays. The AML-linked PU.1 Q218H mutation disrupts PU.1-H2A interactions. Cryo-EM and crystal structure determination of nucleosome complexes, in vitro nucleosome-binding assays, disease mutant analysis Nature structural & molecular biology High 38267599
2014 CTCF and SMARCA5 (ISWI ATPase) are recruited together to the SPI1 gene (including the -14.4 kb enhancer) during normal myeloid differentiation; DNA methylation at the SPI1 locus blocks CTCF binding in AML blasts; upon demethylation, CTCF and SMARCA5 are re-recruited to the SPI1 enhancer. ChIP assays, AZA-mediated demethylation experiments, co-immunoprecipitation, CTCF knockdown/overexpression PloS one Medium 24498324
2001 Histone deacetylase inhibition with trichostatin A down-regulates PU.1 expression at both mRNA and protein levels, causing loss of PU.1 target gene expression (CD11b, c-fms, TLR4, scavenger receptor); ChIP shows increased histone H4 (but not H3) acetylation across ~650 bp of the PU.1 promoter in TSA-treated cells. Trichostatin A treatment of multiple cell lines, Northern/Western blot, chromatin immunoprecipitation Journal of immunology Medium 11673528
2018 PU.1 can bind closed genomic sites in developing T cells and rapidly opens them; effective pioneering at closed chromatin requires non-DNA-binding domains of PU.1 beyond site recognition; PU.1 binding affinity and concentration determine occupancy choices with trade-offs between site sequence quality and chromatin accessibility. Stage-specific gain- and loss-of-function perturbations in pro-T cells, quantitative ChIP-seq, ATAC-seq across PU.1 level dynamics Genome research High 30171019
2012 HK3 (hexokinase 3) is a direct transcriptional target of PU.1: PU.1 binds the HK3 promoter in vivo; PML-RARA attenuates PU.1 activation of the HK3 promoter; HK3 knockdown impairs neutrophil differentiation and viability of APL cells. ChIP, reporter assays, siRNA knockdown, gene expression analysis in APL cell lines and primary samples Blood Medium 22498738
2015 PU.1 directly binds the NFATc1 promoter in osteoclasts and transactivates NFATc1 expression; PU.1 knockdown reduces NFATc1 mRNA, NFATc1 promoter activity, and osteoclast-specific gene expression; enforced PU.1 expression increases NFATc1 and TRAP activity. ChIP, siRNA knockdown, reporter assays, retroviral overexpression, TRAP activity assays in bone marrow-derived osteoclasts Allergology international Medium 26117255
2016 PU.1 directly activates expression of lncRNA HOTAIRM1 through binding to two PU.1 motifs ~+1100 bp downstream of the HOTAIRM1 transcriptional start site; low HOTAIRM1 expression in APL cells is due to reduced PU.1 expression rather than PML-RARα-mediated direct repression. ChIP, reporter assays, ectopic PU.1 expression, gene expression analysis Journal of hematology & oncology Medium 27146823
2021 PU.1 and IRF8 bind an Ets/IRF composite element (EICE) and an Ets motif at the human NLRP3 distal promoter; knockdown of PU.1 and/or IRF8 reduces NLRP3 expression and markedly diminishes LPS-induced IL-1β release, establishing cooperative PU.1-IRF8 control of monocyte-specific NLRP3 inflammasome activity. EMSA, ChIP, siRNA knockdown, reporter assays, IL-1β ELISA in THP-1 cells Frontiers in immunology Medium 33897697
2017 Spi-1/PU.1 overexpression triggers cellular senescence in primary hematopoietic (erythroid and myeloid) cells in a DNA-binding-dependent and p38MAPK14-dependent manner (but independent of DNA-damage response); PU.1 overexpression induces senescence in erythroid bone marrow progenitors in vivo before the pre-leukemic phase. Retroviral overexpression, domain mutants, p38 inhibition, senescence assays (SA-β-gal, Dec1, CDKN1A), Spi-1 transgenic leukemia mouse model, in vivo bone marrow analysis Haematologica Medium 28912174
2009 PU.1 modulates TCR expression in CD4+ T cells by regulating GATA-3's DNA-binding activity and limiting GATA-3's regulation of TCR gene expression; in the absence of PU.1, increased GATA-3 function elevates TCR expression and lowers the T-cell activation threshold. T-cell-specific conditional PU.1 knockout (lck-Cre), flow cytometry, cytokine secretion assays, GATA-3 activity assays Journal of immunology Medium 19801513
2019 Runx1 and PU.1 itself bind the PU.1 upstream regulatory element (URE) in erythroid progenitors; ectopic expression of either Runx1 or PU.1 prevents PU.1 downregulation and blocks terminal erythroid differentiation; Runx1 acting at the URE is required for this block, as ectopic Runx1 fails to block differentiation in BFUe lacking the URE. Ectopic expression, URE deletion mouse model, ChIP, chromatin accessibility (ATAC-seq), ex vivo differentiation assays Proceedings of the National Academy of Sciences of the United States of America High 31431533
2022 Tet2 deficiency combined with heterozygous deletion of the PU.1 upstream regulatory element (35% reduction in PU.1) leads to highly penetrant, transplantable AML; leukemic cells show hypermethylation at PU.1-binding sites and fail to activate myeloid enhancers, uncovering a methylation-sensitive PU.1-dependent gene network as a molecular vulnerability in AML. Compound mouse genetics (Tet2 KO + PU.1 UREΔ/WT), transplantation assays, WGBS, ChIP-seq, ATAC-seq, gene expression profiling Blood cancer discovery High 35820129
2018 EOMES forms a complex with PU.1 and MITF at osteoclast-specific genomic loci as demonstrated by co-immunoprecipitation and sequential ChIP; EOMES knockdown in myeloid precursors leads to osteopetrosis with decreased osteoclast differentiation and function both in vitro and in vivo. Co-immunoprecipitation, sequential ChIP (re-ChIP), EOMES shRNA knockdown, in vitro differentiation, in vivo bone analysis iScience Medium 30634169
2024 PU.1 directly binds the IL-9 promoter to activate its transcription in Th9 cells; Th9-derived IL-9 induces PU.1 expression via the IL-9R-JAK1/STAT3 signaling pathway, forming a positive feedback loop; this loop promotes inflammatory macrophage activation and fibroblast-like synoviocyte hyperactivation in rheumatoid arthritis. ChIP-qPCR, luciferase reporter assay, siRNA knockdown, IL-9 recombinant protein, conditional PU.1 KO mice (CAIA model), collagen-induced arthritis model Annals of the rheumatic diseases Medium 39164066

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. The EMBO journal 906 8896458
1988 Spi-1 is a putative oncogene in virally induced murine erythroleukaemias. Nature 452 2827041
2008 PU.1 and C/EBPalpha/beta convert fibroblasts into macrophage-like cells. Proceedings of the National Academy of Sciences of the United States of America 294 18424555
2019 Salmonella Pathogenicity Island 1 (SPI-1) and Its Complex Regulatory Network. Frontiers in cellular and infection microbiology 259 31428589
1998 PU.1 regulates both cytokine-dependent proliferation and differentiation of granulocyte/macrophage progenitors. The EMBO journal 250 9687512
2005 Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors. The Journal of experimental medicine 249 15657291
2013 Positive feedback between PU.1 and the cell cycle controls myeloid differentiation. Science (New York, N.Y.) 232 23868921
2002 PU.1 regulates expression of the interleukin-7 receptor in lymphoid progenitors. Immunity 229 11869689
1996 Spi-1/PU.1 transgenic mice develop multistep erythroleukemias. Molecular and cellular biology 173 8628313
2019 PU.1 controls fibroblast polarization and tissue fibrosis. Nature 164 30700907
1999 c-Jun is a JNK-independent coactivator of the PU.1 transcription factor. The Journal of biological chemistry 153 9988737
2004 Balance of MafB and PU.1 specifies alternative macrophage or dendritic cell fate. Blood 151 15598817
2008 HilD-mediated transcriptional cross-talk between SPI-1 and SPI-2. Proceedings of the National Academy of Sciences of the United States of America 145 18799744
2007 MITF and PU.1 recruit p38 MAPK and NFATc1 to target genes during osteoclast differentiation. The Journal of biological chemistry 142 17403683
1998 Role of PU.1 in hematopoiesis. Stem cells (Dayton, Ohio) 136 9474745
2002 Crystal structure of PU.1/IRF-4/DNA ternary complex. Molecular cell 132 12453417
2014 The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation. The Journal of experimental medicine 122 25288399
1998 Neutrophils deficient in PU.1 do not terminally differentiate or become functionally competent. Blood 122 9716585
1996 Function of PU.1 (Spi-1), C/EBP, and AML1 in early myelopoiesis: regulation of multiple myeloid CSF receptor promoters. Current topics in microbiology and immunology 119 8585944
1998 The transcription factor Spi-1/PU.1 interacts with the potential splicing factor TLS. The Journal of biological chemistry 117 9478924
2017 Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia. Nature genetics 111 28671687
2015 Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia. Nature medicine 111 26343801
2020 Mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1. Nature communications 105 31964861
2017 Pharmacological inhibition of the transcription factor PU.1 in leukemia. The Journal of clinical investigation 102 29083320
2011 Macrophage development from HSCs requires PU.1-coordinated microRNA expression. Blood 99 21730352
2009 Graded repression of PU.1/Sfpi1 gene transcription by GATA factors regulates hematopoietic cell fate. Blood 90 19491391
2016 MicroRNA-155 influences B-cell function through PU.1 in rheumatoid arthritis. Nature communications 85 27671860
2003 PU.1 and pRB interact and cooperate to repress GATA-1 and block erythroid differentiation. Molecular and cellular biology 85 14559995
2007 PU.1: a crucial and versatile player in hematopoiesis and leukemia. The international journal of biochemistry & cell biology 83 17374502
2013 Knockdown of PU.1 AS lncRNA inhibits adipogenesis through enhancing PU.1 mRNA translation. Journal of cellular biochemistry 77 23749759
2015 The RUNX1-PU.1 axis in the control of hematopoiesis. International journal of hematology 76 25749719
2021 PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress. The Journal of experimental medicine 75 33857288
2010 Surprising new roles for PU.1 in the adaptive immune response. Immunological reviews 72 20969585
2020 Transcription factor PU.1 and immune cell differentiation (Review). International journal of molecular medicine 69 33125129
2018 Transcriptional mechanism of IRF8 and PU.1 governs microglial activation in neurodegenerative condition. Protein & cell 67 30484118
2014 A Comprehensive Profile of ChIP-Seq-Based PU.1/Spi1 Target Genes in Microglia. Gene regulation and systems biology 67 25574134
2005 Role of transcription factors C/EBPalpha and PU.1 in normal hematopoiesis and leukemia. International journal of hematology 65 16158816
2003 The importance of PU.1 concentration in hematopoietic lineage commitment and maturation. Blood cells, molecules & diseases 65 12972030
2018 Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1). Genome research 64 30171019
2007 Is PU.1 a dosage-sensitive regulator of haemopoietic lineage commitment and leukaemogenesis? Trends in immunology 61 17267285
2001 Loss of PU.1 expression following inhibition of histone deacetylases. Journal of immunology (Baltimore, Md. : 1950) 61 11673528
2018 Inflammatory signals directly instruct PU.1 in HSCs via TNF. Blood 59 30301719
2009 PU.1 and partners: regulation of haematopoietic stem cell fate in normal and malignant haematopoiesis. Journal of cellular and molecular medicine 59 19382896
2009 PU.1 regulates TCR expression by modulating GATA-3 activity. Journal of immunology (Baltimore, Md. : 1950) 59 19801513
2000 PU.1/Interferon Regulatory Factor interactions: mechanisms of transcriptional regulation. Cell biochemistry and biophysics 59 11325034
2016 PU.1 cooperates with IRF4 and IRF8 to suppress pre-B-cell leukemia. Leukemia 52 26932576
2000 PU.1 expression in microglia. Journal of neuroimmunology 52 10713349
2021 Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients. The Journal of experimental medicine 51 33951726
2012 PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells. Blood 49 22498738
2016 PU.1 controls the expression of long noncoding RNA HOTAIRM1 during granulocytic differentiation. Journal of hematology & oncology 48 27146823
2019 Safeguard function of PU.1 shapes the inflammatory epigenome of neutrophils. Nature immunology 43 30911105
2014 Epigenetic control of hematopoiesis: the PU.1 chromatin connection. Biological chemistry 43 25205721
2020 Inhibition of PU.1 ameliorates metabolic dysfunction and non-alcoholic steatohepatitis. Journal of hepatology 40 32135178
2013 PU.1 is essential for MLL leukemia partially via crosstalk with the MEIS/HOX pathway. Leukemia 40 24445817
1993 The PU.1/Spi-1 proto-oncogene is a transcriptional regulator of a lentivirus promoter. Journal of virology 39 8389910
2021 Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease. Nature communications 38 33863903
2002 Spi-B can functionally replace PU.1 in myeloid but not lymphoid development. The EMBO journal 37 11980719
2018 Contribution of SPI-1 bistability to Salmonella enterica cooperative virulence: insights from single cell analysis. Scientific reports 36 30291285
1998 PU.1 and hematopoiesis: lessons learned from gene targeting experiments. Seminars in immunology 36 9618756
2017 Epigenomic PU.1-VDR crosstalk modulates vitamin D signaling. Biochimica et biophysica acta. Gene regulatory mechanisms 34 28232093
2015 PU.1 Suppresses Th2 Cytokine Expression via Silencing of GATA3 Transcription in Dendritic Cells. PloS one 34 26361334
2010 CLEC5A (MDL-1) is a novel PU.1 transcriptional target during myeloid differentiation. Molecular immunology 34 21094529
1998 Cooperative interaction between the DNA-binding domains of PU.1 and IRF4. Journal of molecular biology 34 9642085
2019 Cooperation of PU.1 With IRF8 and NFATc1 Defines Chromatin Landscapes During RANKL-Induced Osteoclastogenesis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 32 30721543
2016 Pharmacologic efficacy of PU.1 inhibition by heterocyclic dications: a mechanistic analysis. Nucleic acids research 32 27079976
2009 Transcriptomic profiling identifies a PU.1 regulatory network in macrophages. Biochemical and biophysical research communications 31 19167354
2005 Protein acetylation regulates both PU.1 transactivation and Ig kappa 3' enhancer activity. Journal of immunology (Baltimore, Md. : 1950) 31 16210620
2022 LINC01094/SPI1/CCL7 Axis Promotes Macrophage Accumulation in Lung Adenocarcinoma and Tumor Cell Dissemination. Journal of immunology research 30 36118415
2020 Abnormal expression of colony stimulating factor 1 receptor (CSF1R) and transcription factor PU.1 (SPI1) in the spleen from patients with major psychiatric disorders: A role of brain-spleen axis. Journal of affective disorders 30 32379601
2014 Epigenetic control of SPI1 gene by CTCF and ISWI ATPase SMARCA5. PloS one 30 24498324
2022 Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus. JCI insight 29 35608913
2022 BCL11A promotes myeloid leukemogenesis by repressing PU.1 target genes. Blood advances 28 34714913
2004 Functional analysis of PU.1 domains in monocyte-specific gene regulation. FEBS letters 28 15013752
2011 Sox4 cooperates with PU.1 haploinsufficiency in murine myeloid leukemia. Blood 27 21878674
2000 PU.1 is a lineage-specific regulator of tyrosine phosphatase CD45. The Journal of biological chemistry 27 11114304
2018 Transcription factor PU.1 is involved in the progression of glioma. Oncology letters 26 29467892
2014 The SPI-1-like Type III secretion system: more roles than you think. Frontiers in plant science 26 24575107
2006 Spi-1/PU.1 oncoprotein affects splicing decisions in a promoter binding-dependent manner. The Journal of biological chemistry 25 16698794
2022 HDAC1 and PRC2 mediate combinatorial control in SPI1/PU.1-dependent gene repression in murine erythroleukaemia. Nucleic acids research 24 35871293
2017 Senescence is a Spi1-induced anti-proliferative mechanism in primary hematopoietic cells. Haematologica 24 28912174
2012 Ikaros represses and activates PU.1 cell-type-specifically through the multifunctional Sfpi1 URE and a myeloid specific enhancer. Oncogene 24 22231443
2009 PU.1 activation relieves GATA-1-mediated repression of Cebpa and Cbfb during leukemia differentiation. Molecular cancer research : MCR 24 19825991
2018 Eomes partners with PU.1 and MITF to Regulate Transcription Factors Critical for osteoclast differentiation. iScience 23 30634169
2015 Involvement of PU.1 in NFATc1 promoter function in osteoclast development. Allergology international : official journal of the Japanese Society of Allergology 23 26117255
1999 PU.1 and USF are required for macrophage-specific mannose receptor promoter activity. The Journal of biological chemistry 23 10085160
2021 PU.1 and IRF8 Modulate Activation of NLRP3 Inflammasome via Regulating Its Expression in Human Macrophages. Frontiers in immunology 22 33897697
2009 Essential role of spi-1-like (spi-1l) in zebrafish myeloid cell differentiation. Blood 22 19131555
2023 Human FAM111A inhibits vaccinia virus replication by degrading viral protein I3 and is antagonized by poxvirus host range factor SPI-1. Proceedings of the National Academy of Sciences of the United States of America 21 37607234
2019 LncRNA PU.1 AS regulates arsenic-induced lipid metabolism through EZH2/Sirt6/SREBP-1c pathway. Journal of environmental sciences (China) 21 31471020
2024 Structural mechanism of synergistic targeting of the CX3CR1 nucleosome by PU.1 and C/EBPα. Nature structural & molecular biology 20 38267599
2024 Positive feedback loop PU.1-IL9 in Th9 promotes rheumatoid arthritis development. Annals of the rheumatic diseases 20 39164066
2021 Upregulation of the pathogenic transcription factor SPI1/PU.1 in tuberous sclerosis complex and focal cortical dysplasia by oxidative stress. Brain pathology (Zurich, Switzerland) 20 33786950
2022 PU.1-Dependent Enhancer Inhibition Separates Tet2-Deficient Hematopoiesis from Malignant Transformation. Blood cancer discovery 19 35820129
2015 Nrf2 regulates PU.1 expression and activity in the alveolar macrophage. American journal of physiology. Lung cellular and molecular physiology 19 25840997
2012 Spi-1/PU.1 activates transcription through clustered DNA occupancy in erythroleukemia. Nucleic acids research 19 22790984
2023 Salmonella Enteritidis activates inflammatory storm via SPI-1 and SPI-2 to promote intracellular proliferation and bacterial virulence. Frontiers in cellular and infection microbiology 18 37325511
2024 The role of SPI1/VSIG4/THBS1 on glioblastoma progression through modulation of the PI3K/AKT pathway. Journal of advanced research 17 38960279
2024 SPI1+CD68+ macrophages as a biomarker for gastric cancer metastasis: a rationale for combined antiangiogenic and immunotherapy strategies. Journal for immunotherapy of cancer 17 39455096
2019 Runx1 promotes murine erythroid progenitor proliferation and inhibits differentiation by preventing Pu.1 downregulation. Proceedings of the National Academy of Sciences of the United States of America 17 31431533
2008 CD34, RAB20, PU.1 and GFI1 mRNA expression in myelodysplastic syndrome. International journal of laboratory hematology 17 18371060

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