| 1995 |
LSIRF/IRF4 is a lymphoid-specific member of the IRF family that binds the interferon-stimulated response element (ISRE) of the MHC class I promoter in vitro. Its expression is not induced by interferons but is induced by antigen-receptor-mediated stimuli (plant lectins, CD3, or IgM crosslinking). |
PCR cloning, in vitro DNA binding studies (ISRE binding), lymphoid-cell expression analysis |
Nucleic acids research |
Medium |
7541907
|
| 1996 |
IRF4 (ICSAT/Pip/LSIRF) functions as a transcriptional repressor of interferon-regulated genes. Cotransfection experiments showed IRF4 represses gene activation induced by IFN stimulation or IRF-1 cotransfection, with a distinct repressive activity profile compared to IRF-2 and ICSBP. Differential binding affinities for distinct ICS motifs were established in vitro. |
Cotransfection reporter assays in N-Tera2 cells, in vitro DNA binding affinity comparisons |
Molecular and cellular biology |
Medium |
8657101
|
| 1998 |
The DNA-binding domains of PU.1 and IRF4 form a cooperative ternary complex at immunoglobulin enhancer elements (lambdaB and kappaE3' sites). The minimal IRF4 DNA-binding domain maps to residues 20–137; residues 1–19 decrease IRF4 binding affinity 2- to 5-fold but all constructs bind better in the presence of PU.1's DNA-binding domain. Cooperative interaction requires proper spacing of PU.1 and IRF4 binding sites but is not dependent on phosphorylation of PU.1's PEST domain. NMR indicates the PEST domain of PU.1 and residues 1–19 of IRF4 may be intrinsically unstructured. |
Fluorescence polarization DNA-binding assays, NMR spectroscopy of 15N-labelled constructs, mutagenesis/truncation mapping |
Journal of molecular biology |
High |
9642085
|
| 2002 |
IRF4 can function as both a transcriptional repressor and activator depending on the DNA-binding motif engaged and its protein–protein interaction partners, most notably the Ets family member PU.1. Post-translational modification and nuclear translocation of IRF4 contribute to its transcriptional regulatory role. |
Review integrating prior experimental data (cotransfection assays, DNA-binding studies, nuclear translocation analyses) |
Journal of interferon & cytokine research |
Low |
11846983
|
| 2006 |
IRF4 is required for post-germinal center plasma cell differentiation and for class-switch recombination in B cells. Conditional deletion of Irf4 in germinal center B cells abolished post-GC plasma cells, blocked memory B cell differentiation into plasma cells, impaired AID expression, and eliminated class-switch recombination. IRF4 acts upstream of Blimp-1 and XBP-1 in the plasma cell differentiation cascade. |
Conditional knockout (Cre-lox) in mice, immunological readouts (plasma cell numbers, CSR assays, AID expression), genetic epistasis with Blimp-1 and XBP-1 |
Nature immunology |
High |
16767092
|
| 2008 |
IRF4 directly targets and activates MYC in activated B cells and myeloma, and MYC in turn directly transactivates IRF4, creating an autoregulatory circuit essential for myeloma cell survival. Genome-wide chromatin immunoprecipitation identified an extensive IRF4 target gene network, and RNAi-based genetic screen showed IRF4 knockdown is toxic to myeloma cell lines regardless of transforming oncogenic mechanism. |
RNAi loss-of-function genetic screen, gene expression profiling, genome-wide ChIP analysis, identification of MYC as direct IRF4 target |
Nature |
High |
18568025
|
| 2011 |
IRF4 binds to and activates transcription through the IRF-Ets composite sequence (IECS) in myeloid progenitor cells. Ectopic IRF4 expression inhibits myeloid cell growth, promotes macrophage differentiation, and hinders granulocytic differentiation. Irf8−/−Irf4−/− double-knockout mice develop a more severe CML-like disease than Irf8−/− mice alone, demonstrating functional redundancy between IRF4 and IRF8 in suppressing granulocytic expansion. |
Ectopic expression in myeloid progenitors in vitro, double-knockout mouse model, reporter assays for IECS binding |
PloS one |
Medium |
22003407
|
| 2011 |
IRF4 functions as a tumor suppressor in c-Myc-induced B cell leukemia. IRF4 heterozygous EμMyc mice developed pre-B cell leukemia with greatly accelerated kinetics. IRF4 reconstitution in leukemic cells induced p27kip1 and inhibited their expansion; IRF4-deficient leukemic cells showed loss of p27kip1 expression and inactivation of the wild-type IRF4 allele with Arf-p53 pathway defects. |
EμMyc transgenic mouse model crossed to IRF4+/− mice, IRF4 reconstitution experiments, p27kip1 expression analysis, Arf-p53 pathway assessment |
PloS one |
Medium |
21818355
|
| 2013 |
Smad2/3 and IRF4 cooperatively transactivate the Il9 promoter in Th9 cells. Smad2/3 physically interacts with IRF4 (co-immunoprecipitation), is recruited to the Il9 promoter by TGF-β, and requires IRF4 to activate Il9 transcription; conversely, IRF4 requires Smad2/3 for Il9 promoter binding and Th9 induction. |
T cell-specific Smad2/3 knockout mice, Co-IP of Smad2/3 with IRF4, ChIP at Il9 promoter, IRF4-deficient T cell experiments |
Journal of immunology |
High |
23913959
|
| 2013 |
Low IRF4 expression is causally linked to CLL development: IRF4−/−Vh11 mice develop spontaneous early-onset CLL with 100% penetrance. IRF4 reconstitution in CLL cells inhibits their survival, establishing IRF4 as a causal tumor suppressor in this context. |
IRF4-deficient Vh11 knock-in mouse model, reconstitution of IRF4 in CLL cells, survival/apoptosis assays |
Blood |
Medium |
23926303
|
| 2014 |
IRF4 is a dominant transcriptional driver of thermogenesis in adipocytes, acting as a partner of PGC-1α. IRF4 is induced by cold and cAMP in adipocytes, directly interacts with PGC-1α (Co-IP), induces PGC-1α and PRDM16 expression, and drives Ucp1 expression. Knockout of IRF4 in UCP1+ cells reduces thermogenic gene expression, energy expenditure, and cold tolerance; overexpression promotes all three. PGC-1α-driven thermogenic gene expression requires IRF4. |
Adipocyte-specific IRF4 knockout mice, IRF4 overexpression in vivo, Co-immunoprecipitation of IRF4 with PGC-1α, cold/cAMP stimulation assays, Ucp1 reporter assays |
Cell |
High |
24995979
|
| 2014 |
IRF4 is required in a B cell-intrinsic manner for germinal center B cell formation, independent of its role in plasma cell differentiation. Conditional deletion of Irf4 in mature B cells severely impaired GC formation as early as day 5 post-immunization. IRF4-deficient B cells in chimeric mice failed to participate in GCs after L. major or influenza infection. |
Conditional B cell-specific Irf4 knockout mice, mixed bone marrow chimeras, in vivo immunization models (protein antigen, L. major, influenza) |
Journal of immunology |
High |
24591370
|
| 2014 |
IRF4 and BATF are both necessary for sustained CD8+ T cell effector function after LCMV infection. Irf4−/− CD8+ T cells showed initial proliferation but limited effector responses, causing viral persistence and protection from fatal immunopathology in Irf4−/− mice. Absence of BATF produced a similar phenotype. |
Irf4−/− mouse LCMV infection model, CD8+ T cell functional assays (cytotoxicity, viral clearance), comparison to BATF-deficient mice |
Cell death and differentiation |
Medium |
24531538
|
| 2014 |
IRF4 concentration-dependently controls T helper cell fate: higher IRF4 levels promote Teff (Blimp-1+) fates at the expense of Tfh (Bcl6+) fates. Increased IRF4 abundance leads to its recruitment to lower-affinity binding sites in Teff cis-regulatory elements, including the Prdm1 locus. Orthogonal induction of Irf4 expression redirected Tfh cell fate toward Teff. |
Conditional IRF4 expression systems, ChIP-seq for IRF4 occupancy at distinct binding sites, T cell fate tracing, TCR signal strength manipulation |
Immunity |
High |
28930660
|
| 2016 |
mTORC2 and IL-4Rα-Stat6 pathways operate in parallel to induce IRF4 expression, which in turn drives increased glycolysis necessary for M2 (alternative) macrophage activation. Loss of mTORC2 in macrophages suppressed IRF4 induction and impaired M2 activation including glucose utilization. |
Myeloid-specific mTORC2 knockout mice, IL-4 stimulation assays, IRF4 expression measurements, metabolic flux assays |
Immunity |
High |
27760338
|
| 2016 |
KDM3A maintains expression of KLF2 and IRF4 in multiple myeloma through H3K9 demethylation. KLF2 directly activates IRF4 transcription, and IRF4 reciprocally upregulates KLF2, forming a positive autoregulatory circuit. Knockdown of KDM3A, KLF2, or IRF4 each decreases MM cell adhesion to bone marrow stromal cells and reduces MM cell homing, associated with decreased ITGB7 expression. |
siRNA knockdown, ChIP for H3K9me2 at KLF2/IRF4 loci, luciferase reporter assays for KLF2→IRF4 transcriptional activation, cell adhesion and homing assays |
Nature communications |
High |
26728187
|
| 2016 |
IRF4 and IRF8 cooperate with PU.1 to regulate early B cell development and suppress pre-B cell acute lymphoblastic leukemia. Combined PU.1/IRF4 deletion caused a partial pre-B cell developmental block and 100% leukemia incidence. PU.1/IRF4/IRF8 directly regulate Ikaros and Spi-B, established B-lineage tumor suppressor genes, and restoration of either rescued leukemic cell growth inhibition. |
PU.1/IRF4/IRF8 compound knockout mouse models, ChIP to show direct regulation of Ikaros and Spi-B, reconstitution of Ikaros/Spi-B in leukemic cells |
Leukemia |
High |
26932576
|
| 2017 |
T cell exhaustion during chronic LCMV infection is driven by high TCR-induced IRF4, BATF, and NFATc1. These regulators promote inhibitory receptor expression (including PD-1) and impaired cellular metabolism, while repressing TCF1 required for memory T cell differentiation. Reducing IRF4 expression restored functional and metabolic properties and promoted memory-like T cell development. |
Transcriptional profiling of antigen-specific T cells from acute vs. chronic LCMV infection, IRF4 knockdown/reduction experiments, metabolic assays, inhibitory receptor expression analysis |
Immunity |
High |
29246443
|
| 2017 |
IRF4 represses PD-1 expression and other molecules associated with T cell dysfunction in CD4+ T cells. IRF4 deletion increases chromatin accessibility at PD-1 cis-regulatory elements and enhances Helios binding there, leading to enhanced PD-1 expression and progressive CD4+ T cell dysfunction. The dysfunctional state was initially reversible by PD-1 ligand blockade. |
Irf4 conditional deletion in T cells, ATAC-seq for chromatin accessibility, ChIP for Helios at PD-1 cis-regulatory elements, allograft transplant model |
Immunity |
High |
29221730
|
| 2017 |
ITK kinase activity is required for Tr1 cell differentiation via the Ras/IRF4 pathway. Downstream of ITK, Ras activity induces IRF4 expression; constitutively active HRas rescues IRF4 expression and Tr1 cell differentiation in Itk−/− cells. IRF4 expression in Itk-deficient cells restores Tr1 cell development and suppressive function. |
Itk-deficient mouse model, constitutively active HRas rescue experiments, IRF4 reconstitution in Itk−/− cells, in vitro Tr1 cell differentiation assays |
Nature communications |
Medium |
28635957
|
| 2018 |
The K59R IRF4 mutant found in adult T-cell leukemia is expressed at higher levels in the nucleus than WT IRF4 and is transcriptionally more active. IRF4 is bound to genomic regulatory DNA of its transcriptional targets in HTLV-1-transformed cell lines. Overexpression of both WT and K59R IRF4 from a constitutive promoter in murine bone marrow cells increased T lymphocyte abundance in vivo. |
Whole-exome sequencing, ChIP of IRF4 at target loci in HTLV-1-transformed cells, nuclear/cytoplasmic fractionation comparing WT vs K59R, retroviral transduction of murine bone marrow |
The Journal of biological chemistry |
Medium |
29540473
|
| 2019 |
IRF4 activity in established plasma cells is required to regulate gene transcription specifying plasma cell identity and maintaining mitochondrial homeostasis. IRF4 loss in mature plasma cells triggers apoptosis, but this is not through direct regulation of the intrinsic apoptotic pathway; rather, inducible IRF4 deletion in the presence of BCL2 overexpression revealed the transcriptional (identity/mitochondrial) functions of IRF4 separately from its pro-survival role. |
Inducible Irf4 deletion system combined with BCL2 overexpression, gene expression profiling, mitochondrial function assays |
Cell reports |
Medium |
31775034
|
| 2020 |
IRF4 and NF-κB co-occupy super-enhancers in ATL cells and form a coherent feed-forward loop to coordinately regulate T-cell functional/developmental genes, as well as cancer-associated genes including MYC, CCR4, and BIRC3. Genetic inhibition of BIRC3 (a downstream effector) induced growth inhibition in ATL cells. |
Gene expression profiling of primary ATL samples, ChIP-seq for IRF4 and NF-κB binding at super-enhancers, BIRC3 genetic knockdown, growth inhibition assays |
Blood |
Medium |
31972002
|
| 2020 |
IRF4, either alone or in combination with BATF, directly controls a molecular program responsible for immunosuppression of CD4+ effector Tregs in tumors. Integration of transcriptomic and epigenomic data demonstrated direct IRF4 (and IRF4/BATF composite) binding at suppressive molecule gene loci; Irf4 deletion exclusively in Tregs delayed tumor growth in mice. |
Single-cell profiling, integration of transcriptomics and epigenomics (ATAC-seq/ChIP), Irf4 Treg-specific conditional knockout mouse tumor model |
The Journal of clinical investigation |
High |
32125291
|
| 2021 |
Crystal structure of the IRF4/ISRE homodimeric complex revealed that homodimer formation is achieved exclusively through protein-DNA contacts with substantial DNA deformation, with no direct protein-protein contact. This contrasts with the IRF4/PU.1 heterodimeric complex where DNA-bound IRF4 physically contacts PU.1 to engage EICE1. Hotspot residues Arg98, Cys99, and Asn102 contact both consensus and non-consensus sequences via a flexible L1 loop. The CLL-associated IRF4L116R mutant binds DNA more robustly, providing a structural rationale for its gain-of-function. |
X-ray crystallography (crystal structure of IRF4/ISRE homodimer), mutagenesis of hotspot residues, comparison with heterodimeric complex |
Nucleic acids research |
High |
33533913
|
| 2021 |
BATF and IRF4 cooperate to counter T cell exhaustion in tumor-infiltrating CAR T cells. BATF overexpression in CAR T cells promoted survival, effector cytokine production, decreased inhibitory receptor/TOX expression, and supported memory T cell generation. These responses required BATF-IRF4 interaction, as a BATF variant unable to interact with IRF4 failed to improve antitumor responses. |
CAR T cell mouse tumor models, BATF overexpression, BATF mutant unable to interact with IRF4 (domain interaction requirement), flow cytometry, tumor growth assays |
Nature immunology |
High |
34282330
|
| 2021 |
IRF4 negatively regulates BCR signaling in CLL cells by reducing AKT and ERK phosphorylation and calcium release; it suppresses expression of SYK (a key BCR signaling kinase) and IKAROS. IKAROS in turn promotes BCR signaling by reducing SHIP1 expression. IMiDs (lenalidomide/avadomide) induce IRF4 expression while down-regulating IKAROS, interfering with BCR-triggered survival advantage. |
IRF4 overexpression and siRNA knockdown in CLL cells, phospho-flow cytometry for AKT/ERK, calcium flux assays, SYK and IKAROS expression measurements, SHIP1 expression analysis |
Leukemia |
Medium |
33623139
|
| 2021 |
PC4, IKAROS, and IRF4 form a complex in mature B cells (Co-IP). IRF4 reciprocally induces PC4 expression via a super-enhancer. PC4 is required for IRF4 protein to increase upon B cell activation; PC4-deficient B cells show impaired plasma cell generation. |
B cell-specific PC4 knockout mice, Co-IP of PC4/IKAROS/IRF4 complex, super-enhancer analysis by ChIP, plasma cell differentiation assays |
Cell reports |
Medium |
33357426
|
| 2023 |
A heterozygous IRF4 mutation (p.T95R) in the DNA-binding domain causes autosomal dominant combined immunodeficiency by acting as a multimorphic allele: it binds DNA with higher affinity than WT (gain-of-function hypermorph), has reduced transcriptional activity on canonical IRF4 target genes (hypomorphic), and binds noncanonical DNA sites to alter gene expression (neomorphic). IRF4T95R alters B cell maturation, immunoglobulin isotype switching, plasma cell differentiation, and TH17/TFH T cell populations. |
Patient genetics, knock-in mouse model of T95R, DNA binding affinity assays, transcriptomic profiling of patient cells, motif analysis of canonical vs. noncanonical binding sites |
Science immunology |
High |
36662884
|
| 2023 |
A heterozygous IRF4 missense variant in the interferon activation domain causes dominant primary immunodeficiency by altering IRF4 protein-protein interactions (identified by rapid immunoprecipitation mass spectrometry of endogenous proteins). Mutant IRF4 fails to efficiently regulate ISRE transcriptional activity and reduces BLIMP-1 and XBP1 expression, blocking plasma cell differentiation. |
Patient genetics, immunoprecipitation mass spectrometry of endogenous IRF4 protein partners, ISRE reporter assays, BLIMP-1/XBP1 expression in patient B cell lines |
The Journal of experimental medicine |
Medium |
36917008
|
| 2023 |
IRF4 in skeletal muscle transcriptionally regulates FSTL1 expression (established by dual luciferase reporter assay). Muscle-secreted FSTL1 acts on liver cells via distinct receptors (DIP2A/CD14) to regulate hepatic steatosis, inflammation, and fibrosis, defining an IRF4-FSTL1-DIP2A/CD14 inter-organ endocrine axis in NASH. |
Skeletal muscle-specific IRF4 knockout mice, proteomics, dual luciferase reporter assay for IRF4→FSTL1 transcription, co-culture experiments, AAV-mediated FSTL1 rescue in F4MKO mice |
Nature communications |
High |
37770480
|
| 2023 |
IRF4 functions as a signal integrator in NK cells during cytomegalovirus infection, coordinating nutrient uptake (glucose and amino acid transport) necessary for NK cell expansion, differentiation, and memory generation. IRF4-deficient virus-specific NK cells were impaired in nutrient uptake and failed to expand or form memory. |
Irf4 conditional knockout in NK cells, MCMV infection model, nutrient uptake assays (glucose/amino acid transport), clonal expansion and memory NK cell assays |
Nature immunology |
Medium |
37697097
|
| 2023 |
The somatic mutation IRF4-C99R in Hodgkin lymphoma causes a fundamental alteration of IRF4 DNA binding: loss of binding to canonical IRF motifs and neomorphic gain of binding to canonical and non-canonical IRF composite elements (AICEs). IRF4-C99R blocks IRF4-dependent plasma cell induction and upregulates disease-specific genes in a non-canonical AICE-dependent manner. |
ChIP-seq of IRF4-C99R vs. WT in lymphoma cells, gene expression profiling, plasma cell differentiation assays, AICE motif analysis |
Nature communications |
High |
37935654
|
| 2024 |
ARID1A, a SWI/SNF complex member, is required for IRF4 expression in multiple myeloma and physically associates with IRF4 on chromatin. Deleting Arid1a in activated murine B cells disrupts IRF4-dependent transcriptional networks and blocks plasma cell differentiation. SWI/SNF inhibition causes rapid loss of IRF4-target gene expression and quenches MYC-driven oncogenic gene amplification. |
Multi-omics (functional genomics screening, spatial proteomics, chromatin mapping), co-occupancy of ARID1A and IRF4 by ChIP, Arid1a conditional KO in B cells, SMARCA2/4 inhibitor experiments |
Cancer cell |
High |
38906156
|
| 2018 |
PU.1 and IRF4 form a heterodimer that synergistically transactivates the Aldh1a2 (RALDH2) gene via an EICE motif at −1961/−1952 in dendritic cells. ChIP assays confirmed that both PU.1 and IRF4 bind the Aldh1a2 gene ~2 kb upstream of the TSS in bone marrow-derived and ex vivo DCs. Knockdown of either factor reduced RALDH2 mRNA and enzymatic activity. |
ChIP assay, EMSA, luciferase reporter assay, siRNA knockdown in BMDCs, ex vivo DC analysis |
Journal of immunology |
Medium |
30413670
|
| 2021 |
IRAK4 phosphorylates both IRF4 and IRF5 in microglia, and forms a Myddosome complex with MyD88/IRF5/IRF4. Phosphorylated IRF4 translocates to the nucleus to drive anti-inflammatory microglial responses. IRAK4 inhibition blocks IRF4/IRF5 phosphorylation, reduces pro-inflammatory response, and increases neuronal viability after ischemia. |
Co-immunoprecipitation/Western blot of Myddosome complex, IRAK4 inhibitor treatment, nuclear translocation assays, OGD model in microglial cells |
Cells |
Medium |
33573200
|
| 2020 |
IRF4 in skeletal muscle regulates glycogen metabolism by transcriptionally controlling PTG (protein targeting to glycogen). IRF4 knockout in skeletal muscle increases glycogen content and exercise capacity; IRF4 overexpression decreases both. PTG knockdown reverses the effects of IRF4 absence in vivo. |
Skeletal muscle-specific IRF4 knockout and overexpression mice, PTG knockdown in vivo, glycogen content measurements, exercise capacity assays |
Advanced science |
Medium |
33042761
|