Alternative titles; symbols
HGNC Approved Gene Symbol: IRF4
Cytogenetic location: 6p25.3 Genomic coordinates (GRCh38): 6:391,752-411,443 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p25.3 | [Skin/hair/eye pigmentation, variation in, 8] | 611724 | 3 |
IRF4 is a transcription factor essential for the development of T helper-2 (Th2) cells, IL17 (see 603149)-producing Th17 cells, and IL9 (146931)-producing Th9 cells (Staudt et al., 2010).
Grossman et al. (1996) cloned a novel human interferon regulatory factor (IRF) that they named LSIRF for 'lymphocyte-specific IRF.' They reported that the gene encodes a 450-amino acid polypeptide with a predicted mass of 51.6 kD. The gene is expressed as a single 5-kb transcript in spleen, lymphocytes, and melanocytes.
Grossman et al. (1996) found that expression of LSIRF was induced in T cells after crosslinking of the T-cell receptor (see 186880).
By fluorescence and confocal microscopy, Negishi et al. (2005) demonstrated that IRF4 interacted with MYD88 (602170) in the cytoplasm of human embryonic kidney cells. Mutation and coimmunoprecipitation analysis showed that IRF4 interacted with the TIR/IL1 region of MYD88. IRF4 inhibited interaction of MYD88 with IRF5 (607218), which interacts with the same central region of MYD88 as IRF4, but it did not block interaction of MYD88 with IRF7 (605047), which binds to the N terminus. IRF5-dependent gene induction was inhibited by IRF4, and IRF4-deficient macrophages were hyperresponsive to Toll-like receptor (TLR; see 603030) stimuli. Negishi et al. (2005) concluded that IRF4 negatively regulates TLR signaling by selectively competing with IRF5.
Shaffer et al. (2008) used a loss-of-function, RNA interference-based genetic screen to demonstrate that IRF4 inhibition is toxic to myeloma cell lines, regardless of transforming oncogenic mechanism. Gene expression profiling and genomewide chromatin immunoprecipitation analysis uncovered an extensive network of IRF4 target genes and identified MYC (190080) as a direct target of IRF4 in activated B cells and myeloma. Unexpectedly, IRF4 was itself a direct target of MYC transactivation, generating an autoregulatory circuit in myeloma cells. Shaffer et al. (2008) suggested that although IRF4 is not genetically altered in most myelomas, they are nonetheless addicted to an aberrant IRF4 regulatory network that fuses the gene expression programs of normal plasma cells and activated B cells.
Zheng et al. (2009) showed that in mouse T regulatory cells, high amounts of IRF4, a transcription factor essential for TH2 effector cell differentiation, is dependent on Foxp3 (300292) expression. They proposed that IRF4 expression endows T regulatory cells with the ability to suppress TH2 responses. Indeed, ablation of a conditional Irf4 allele in T regulatory cells resulted in selective dysregulation of TH2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear cell-dominated pathology typical of mice lacking T regulatory cells. Zheng et al. (2009) concluded that T regulatory cells use components of the transcriptional machinery, promoting a particular type of effector CD4+ T cell differentiation, to efficiently restrain the corresponding type of the immune response.
Staudt et al. (2010) found that Cd4 (186940)-positive T cells from Irf4 -/- mice failed to differentiate into Il9-producing Th9 cells in the presence of Tgfb (190180) and Il4 (147780). Treatment of Cd4-positive T cells with Irf4 small interfering RNA strongly reduced Il9 production and enhanced Ifng (147570) expression, but had no effect on Il2 (147680) production. Reporter gene analysis demonstrated that Irf4 bound directly to the Il9 promoter. Naive human CD4-positive T cells stimulated with IL4 and TGFB also differentiated into Th9 cells, and this was accompanied by strong expression of IRF4. Staudt et al. (2010) concluded that IRF4 is essential for development of Th9 cells.
By flow cytometric analysis, Cretney et al. (2011) demonstrated that Blimp1 (PRDM1; 603423) was expressed in a subset of mouse regulatory T cells (Tregs) that localized mainly to mucosal sites and expressed Il10 (124092) in a Blimp1-dependent manner. Blimp1 was also required for tissue homeostasis. Irf4, but not Tbet (TBX21; 604895), was essential for Blimp1 expression and for differentiation of all effector Tregs. Cretney et al. (2011) concluded that the differentiation pathway that leads to the acquisition of Treg effector functions requires both IRF4 and BLIMP1.
Li et al. (2012) showed that in mouse CD4+ T cells and B cells IRF4 unexpectedly can cooperate with activator protein-1 (AP1; see 165160) complexes to bind to AP1-IRF4 composite (5-prime-TGAnTCA/GAAA-3-prime) motifs that they denoted as AP1-IRF composite elements (AICEs). Moreover, BATF-JUN family protein complexes cooperate with IRF4 in binding to AICEs in preactivated CD4+ T cells stimulated with IL21 (605384) and in TH17 differentiated cells. Importantly, BATF (612476) binding was diminished in Irf4-null T cells and IRF4 binding was diminished in Batf-null T cells, consistent with functional cooperation between these factors. Moreover, Li et al. (2012) showed that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in TH17 cells and potently regulated by IL21. Li et al. (2012) concluded that their findings revealed that IRF4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context.
Using chromatin immunoprecipitation sequencing in T-helper-17 (TH17) cells, Glasmacher et al. (2012) found that IRF4 targets sequences enriched for activated protein-1 (AP1; 165160)-IRF composite elements (AICEs) that are cobound by BATF (612476), an AP1 factor required for TH17, B, and dendritic cell differentiation. IRF4 and BATF bind cooperatively to structurally divergent AICEs to promote gene activation and TH17 differentiation. The AICE motif directs assembly of IRF4 or IRF8 (601565) with BATF heterodimers and is also used in TH2, B, and dendritic cells. Glasmacher et al. (2012) concluded that this genomic regulatory element and cognate factors appear to have evolved to integrate diverse immunomodulatory signals.
In human and mouse melanocytes, Praetorius et al. (2013) found that MITF (156845) and TFAP2A (107580) cooperatively activate IRF4 expression through an enhancer element in intron 4. In turn, IRF4 cooperates with MITF to regulate expression of TYR (606933). In melanoblasts isolated from mice, Praetorius et al. (2013) found that Mitf, Tfap2a, and Tyr were expressed at the embryonic and postnatal stages, but Irf4 was expressed only at the postnatal stages, suggesting that Irf4 is mostly involved in melanocyte differentiation. Tyr expression increased significantly during the postnatal stages.
Using mouse and human brown adipose tissue (BAT), Kong et al. (2014) found that IRF4 was transcriptionally regulated not only by fasting but also by exposure to cold prior to the induction of UCP1 (113730). Mice overexpressing Irf4 in BAT displayed enhanced thermogenic gene expression, energy expenditure, and cold tolerance. Mice lacking Irf4 specifically in Ucp1-positive cells were obese and insulin resistant, and they displayed reduced thermogenic gene expression, cold tolerance, and energy expenditure. Irf4 expression also induced expression of both Pgc1a (604517) and Prdm16 (605557), and Irf4 interacted with Pgc1a to induce Ucp1 expression. In the absence of Irf4, even with forced expression of Pgc1a, cold catecholamines were unable to induce thermogenic gene expression. Kong et al. (2014) concluded that IRF4 acts as a dominant transcriptional regulator of thermogenesis via genetic and physical interactions with PGC1A.
Using fluorescence in situ hybridization, Grossman et al. (1996) mapped the LSIRF gene to chromosome 6p25-p23.
Association with Chronic Lymphocytic Leukemia
In a genomewide association study to identify common variants influencing the risk of developing chronic lymphocytic leukemia (CLL; see 151400), Di Bernardo et al. (2008) found the strongest association with 2 single-nucleotide polymorphisms (SNPs) that mapped to a 97-kb block of linkage disequilibrium on chromosome 6p25.3 (CLLS4; 612558) that contains the IRF4 gene. The SNP rs872071 maps within the 3-prime untranslated region of IRF4. The overall estimate of effect associated with rs872071 was an odds ratio trend of 1.54 with a 95% confidence interval of 1.41 to 1.69 and a P value of 1.91 x 10(-20). The genotype at SNP rs872071 was sufficient to capture all of the locus variation. Di Bernardo et al. (2008) considered IRF4 a strong candidate gene for a CLL susceptibility a priori, being a key regulator of lymphocyte development and proliferation. In studies using Epstein-Barr virus (EBV)-transformed lymphocytes, expression of IRF4 mRNA was significantly associated with genotype in a dose-dependent fashion (p = 0.042), with lower expression associated with risk alleles. Di Bernardo et al. (2008) argued that this observation is consistent with a model in which the causal variant influences risk by arresting transition of memory B cells through decreased IRF4 expression.
Using a set of SNP markers, Crowther-Swanepoel et al. (2010) generated a fine-scale map of 6p25.3 and narrowed the signal for association with CLL to an 18-kb DNA segment within the 3-prime untranslated region (UTR) of IRF4. Resequencing this segment in European subjects identified 55 common polymorphisms, including 13 highly correlated candidate causal variants. In a large case-control study, it was shown that all but 4 variants could be excluded with 95% confidence. These 4 SNPs mapped to a 3-kb region of the 3-prime UTR of IRF4, consistent with the causal basis of the association being differential IRF4 expression.
In multiple myeloma (254500), chromosomal translocations affecting 14q32 and unidentified partner chromosomes are common, suggesting that they may cause the activation of novel oncogenes. In multiple myeloma cell lines, Iida et al. (1997) identified a t(6;14)(p25;q32) translocation in 2 of 11 cell lines. The translocation juxtaposes the immunoglobulin heavy-chain (IGHG1; 147100) locus to the MUM1 (for 'multiple myeloma oncogene 1') gene, which is also referred to as interferon regulatory factor-4 (IRF4), a member of a gene family known to be active in the control of B-cell proliferation and differentiation. See IRF1 (147575) on chromosome 5 and IRF2 (147576) on chromosome 4. As a result of the translocation, the MUM1/IRF4 gene is overexpressed, an event that may contribute to tumorigenesis, as Iida et al. (1997) showed that MUM1/IRF4 has oncogenic activity in vitro.
In a multistage GWAS of 4 studies comprising 7,028 individuals of European ancestry, Han et al. (2008) found significant association between skin/hair/eye pigmentation-8 (SHEP8; 611724) and an intronic C-to-T SNP (rs12203592; 601900.0001) in the IRF4 gene.
Praetorius et al. (2013) stated that the T minor allele of rs12203592 is not seen in sub-Saharan Africans or East Asians, and is most common in individuals of European descent. Among 2,230 Icelanders, there was a strong association between the T allele and the presence of freckles, brown hair, and high sensitivity of skin to sun exposure; a lesser association was found with eye color. In vitro functional expression studies in mouse and human melanin-containing cells showed that the SNP altered the function of the melanocyte enhancer in IRF4 by disrupting a TFAP2A (107580)-binding site, thereby suppressing the induction of IRF4 expression and impairing the induction of TYR.
By knocking out exons 2 and 3 of the Irf4 gene, Mittrucker et al. (1997) generated mice deficient in Irf4 protein. Flow cytometric analysis indicated normal expression of bone marrow and immature B-lymphocyte markers. After 4 to 5 weeks of age, the mutant mice began to develop generalized lymphadenopathy with expansion of both T and B lymphocytes, failed to develop germinal centers in B-cell follicles or plasma cells after immunization, had poor T- and B-lymphocyte proliferative responses after stimulation with most mitogens, lacked production of all serum Ig subclasses after immunization with T cell-dependent or -independent antigens, and were unable to reject mastocytoma cells. Mittrucker et al. (1997) concluded that IRF4 is essential for mature T- and B-lymphocyte function.
Negishi et al. (2005) found that mice lacking Irf4 displayed a more potent and lethal inflammatory response to CpG oligonucleotides, underscoring the role of IRF4 as a critical negative regulator of TLR signaling.
Honma et al. (2005) showed that Irf4 -/- mice were sensitive to TLR stimulation, such as lipopolysaccharide-induced shock. Irf4 -/- macrophages produced high levels of Tnf (191160) and Il6 (147620) in response to TLR ligands. Small interfering RNA against Irf4 in normal macrophages inhibited the inflammatory response. Honma et al. (2005) concluded that IRF4 negatively regulates TLR signaling and inhibits proinflammatory cytokine production.
Staudt et al. (2010) found that transfer of either Th2 or Th9 cells to Rag2 (179616)-deficient mice resulted in severe asthma symptoms. In mice that had received Th9 cells, but not Th2 cells, these symptoms could be relieved with anti-Il9. Mice lacking Irf4, which is essential for Th9 cell development, were resistant to development of asthma, while Irf4 +/- heterozygotes had an intermediate phenotype. Staudt et al. (2010) concluded that Th9 cell-derived IL9 is an important inducer of asthmatic symptoms, equivalent to that caused by Th2 cells and IL4.
New Zealand Black (NZB) mice naturally develop late-onset CLL, typically around 12 months of age, with the malignant CLL clones derived from B1 cells. Ma et al. (2013) generated Irf4 heterozygous mutant mice on an NZB background (NZB Irf4 +/- mice). They found that CLL cells could be detected at 3 months of age in some NZB Irf4 +/- mice, and that 80% of NZB Irf4 +/- mice developed CLL by 5 months of age. Irf4 +/- B1 cells exhibited prolonged survival, accelerated self-renewal, and defects in differentiation. NZB Irf4 +/- cells were resistant to apoptosis, but high levels of Irf4 inhibited their survival, an effect also seen in human leukemia cell lines. High levels of Irf4 suppressed Akt (164730) activity in a manner independent of the Irf4 DNA-binding domain. Ma et al. (2013) concluded that there is a causal relationship between low levels of IRF4 and development of CLL and that IRF4 is a regulator of CLL pathogenesis.
Ochiai et al. (2013) generated mixed bone marrow chimeras with mouse Irf4 +/+ and Irf4 -/- progenitors and found that B220 (PTPRC; 151460)-positive cells from the knockout mice did not express the germinal center (GC) markers Cd95 (TNFRSF6; 134637) and Gl7, leading to a lack of cells expressing Bcl6 (109565). Transient expression of Irf4 in mice induced expression of key GC genes, including Bcl6 and Aicda (605257). However, sustained expression with higher concentrations of Irf4 antagonized GC fate and promoted generation of plasma cells. Irf4 shared Ets (164720) or Ap1 (165160) binding sites with Pu.1 (SPI1; 165170) or Batf (612476). At higher concentrations, Irf4 binding shifted to interferon sequence response elements, and these enriched for genes involved in plasma cell differentiation. Ochiai et al. (2013) proposed a model of kinetic control in which signaling-induced dynamics of IRF4 in activated B cells controls their cell-fate outcomes.
In a multistage GWAS of 4 studies comprising 7,028 individuals of European ancestry, Han et al. (2008) found significant association between skin/hair/eye pigmentation-8 (SHEP8; 611724) and a C-to-T SNP (rs12203592) in the IRF4 gene. The association was strongest for brown hair color (p = 7.46 x 10(-127)), followed by skin color (p = 6.2 x 10(-14)), and eye color (p = 6.1 x 10(-13)). There was also a strong association with skin tanning response to sunlight (p = 3.9 x 10(-89)). A multivariable analysis pooling data from the initial GWAS and an additional 1,440 individuals suggested that the association between rs12203592 and hair color was independent of rs1540771.
Praetorius et al. (2013) stated that the T minor allele of rs12203592, which is located in intron 4 of the IRF4 gene, is not seen in sub-Saharan Africans or East Asians, and is most common in individuals of European descent. Among 2,230 Icelanders, there was a strong association between the T allele and the presence of freckles, brown hair, and high sensitivity of skin to sun exposure; a lesser association was found with eye color. In vitro functional expression studies in mouse and human melanin-containing cells showed that the C allele of rs12203592 lies within an enhancer of IRF4 transcription. Similar results were found in zebrafish studies. The T allele of this SNP alters the function of the melanocyte enhancer in IRF4 by disrupting a TFAP2A (107580)-binding site, thereby suppressing the induction of IRF4 expression and impairing the induction of TYR (606993). In addition, IRF4 protein levels were reduced in cells from T/T individuals compared to C/C individuals.
Using cultured skin melanocytes derived from individuals with differently pigmented skin and 2 melanoma cell lines, Visser et al. (2015) found that the C allele of rs12203592 formed a long-range chromatin loop that interacted with the IRF4 promoter region. This interaction strongly correlated with open chromatin characteristics and IRF4 expression. The T allele of rs12203592 was associated with closed chromatin conformation in the promoter region. Visser et al. (2015) also identified a potential regulatory element in a small conserved region of intron 7 of the IRF4 gene that included binding sites for transcription factor YY1 (600013). A chromatin loop that formed between the intron 7 site and the C allele of rs12203592 appeared to stabilize the open chromatin conformation for enhanced IRF4 transcription in melanocytes.
Cretney, E., Xin, A., Shi, W., Minnich, M., Masson, F., Miasari, M., Belz, G. T., Smyth, G. K., Busslinger, M., Nutt, S. L., Kallies, A. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nature Immun. 12: 304-311, 2011. [PubMed: 21378976] [Full Text: https://doi.org/10.1038/ni.2006]
Crowther-Swanepoel, D., Broderick, P., Ma, Y., Robertson, L., Pittman, A. M., Price, A., Twiss, P., Vijayakrishnan, J., Quereshi, M., Dyer, M. J. S., Matutes, E., Dearden, C., Catovsky, D., Houlston, R. S. Fine-scale mapping of the 6p25.3 chronic lymphocytic leukaemia susceptibility locus. Hum. Molec. Genet. 19: 1840-1845, 2010. [PubMed: 20123861] [Full Text: https://doi.org/10.1093/hmg/ddq044]
Di Bernardo, M. C., Crowther-Swanepoel, D., Broderick, P., Webb, E., Sellick, G., Wild, R., Sullivan, K., Vijayakrishnan, J., Wang, Y., Pittman, A. M., Sunter, N. J., Hall, A. G., and 17 others. A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nature Genet. 40: 1204-1210, 2008. [PubMed: 18758461] [Full Text: https://doi.org/10.1038/ng.219]
Glasmacher, E., Agrawal, S., Chang, A. B., Murphy, T. L., Zeng, W., Vander Lugt, B., Khan, A. A., Ciofani, M., Spooner, C. J., Rutz, S., Hackney, J., Nurieva, R., Escalante, C. R., Ouyang, W., Littman, D. R., Murphy, K. M., Singh, H. A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes. Science 338: 975-980, 2012. [PubMed: 22983707] [Full Text: https://doi.org/10.1126/science.1228309]
Grossman, A., Mittrucker, H.-W., Nicholl, J., Suzuki, A., Chung, S., Antonio, L., Suggs, S., Sutherland, G. R., Siderovski, D. P., Mak, T. W. Cloning of human lymphocyte-specific interferon regulatory factor (hLSIRF/hIRF4) and mapping of the gene to 6p23-p25. Genomics 37: 229-233, 1996. [PubMed: 8921401] [Full Text: https://doi.org/10.1006/geno.1996.0547]
Han, J., Kraft, P., Nan, H., Guo, Q., Chen, C., Qureshi, A., Hankinson, S. E., Hu, F. B., Duffy, D. L., Zhao, Z. Z., Martin, N. G., Montgomery, G. W., Hayward, N. K., Thomas, G., Hoover, R. N., Chanock, S., Hunter, D. J. A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation. PLoS Genet. 4: e1000074, 2008. Note: Electronic Article. [PubMed: 18483556] [Full Text: https://doi.org/10.1371/journal.pgen.1000074]
Honma, K., Udono, H., Kohno, T., Yamamoto, K., Ogawa, A., Takemori, T., Kumatori, A., Suzuki, S., Matsuyama, T., Yui, K. Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS. Proc. Nat. Acad. Sci. 102: 16001-16006, 2005. [PubMed: 16243976] [Full Text: https://doi.org/10.1073/pnas.0504226102]
Iida, S., Rao, P. H., Butler, M., Corradini, P., Boccadoro, M., Klein, B., Chaganti, R. S. K., Dalla-Favera, R. Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma. Nature Genet. 17: 226-230, 1997. [PubMed: 9326949] [Full Text: https://doi.org/10.1038/ng1097-226]
Kong, X., Banks, A., Liu, T., Kazak, L., Rao, R. R., Cohen, P., Wang, X., Yu, S., Lo, J. C., Tseng, Y.-H., Cypess, A. M., Xue, R., Kleiner, S., Kang, S., Spiegelman, B. M., Rosen, E. D. IRF4 is a key thermogenic transcriptional partner of PGC-1-alpha. Cell 158: 69-83, 2014. [PubMed: 24995979] [Full Text: https://doi.org/10.1016/j.cell.2014.04.049]
Li, P., Spolski, R., Liao, W., Wang, L., Murphy, T. L., Murphy, K. M., Leonard, W. J. BATF-JUN is critical for IRF4-mediated transcription in T cells. Nature 490: 543-546, 2012. [PubMed: 22992523] [Full Text: https://doi.org/10.1038/nature11530]
Ma, S., Shukla, V., Fang, L., Gould, K. A., Joshi, S. S., Lu, R. Accelerated development of chronic lymphocytic leukemia in New Zealand Black mice expressing a low level of interferon regulatory factor 4. J. Biol. Chem. 288: 26430-26440, 2013. [PubMed: 23897826] [Full Text: https://doi.org/10.1074/jbc.M113.475913]
Mittrucker, H.-W., Matsuyama, T., Grossman, A., Kundig, T. M., Potter, J., Shahinian, A., Wakeham, A., Patterson, B., Ohashi, P. S., Mak, T. W. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275: 540-543, 1997. [PubMed: 8999800] [Full Text: https://doi.org/10.1126/science.275.5299.540]
Negishi, H., Ohba, Y., Yanai, H., Takaoka, A., Honma, K., Yui, K., Matsuyama, T., Taniguchi, T., Honda, K. Negative regulation of Toll-like-receptor signaling by IRF-4. Proc. Nat. Acad. Sci. 102: 15989-15994, 2005. [PubMed: 16236719] [Full Text: https://doi.org/10.1073/pnas.0508327102]
Ochiai, K., Maienschein-Cline, M., Simonetti, G., Chen, J., Rosenthal, R., Brink, R., Chong, A. S., Klein, U., Dinner, A. R., Singh, H., Sciammas, R. Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4. Immunity 38: 918-929, 2013. [PubMed: 23684984] [Full Text: https://doi.org/10.1016/j.immuni.2013.04.009]
Praetorius, C., Grill, C., Stacey, S. N., Metcalf, A. M., Gorkin, D. U., Robinson, K. C., Van Otterloo, E., Kim, R. S. Q., Bergsteinsdottir, K., Ogmundsdottir, M. H., Magnusdottir, E., Mishra, P. J., and 21 others. A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. Cell 155: 1022-1033, 2013. [PubMed: 24267888] [Full Text: https://doi.org/10.1016/j.cell.2013.10.022]
Shaffer, A. L., Emre, N. C. T., Lamy, L., Ngo, V. N., Wright, G., Xiao, W., Powell, J., Dave, S., Yu, X., Zhao, H., Zeng, Y., Chen, B., Epstein, J., Staudt, L. M. IRF4 addiction in multiple myeloma. Nature 454: 226-231, 2008. [PubMed: 18568025] [Full Text: https://doi.org/10.1038/nature07064]
Staudt, V., Bothur, E., Klein, M., Lingnau, K., Reuter, S., Grebe, N., Gerlitzki, B., Hoffmann, M., Ulges, A., Taube, C., Dehzad, N., Becker, M., Stassen, M., Steinborn, A., Lohoff, M., Schild, H., Schmitt, E., Bopp, T. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33: 192-202, 2010. [PubMed: 20674401] [Full Text: https://doi.org/10.1016/j.immuni.2010.07.014]
Visser, M., Palstra, R.-J., Kayser, M. Allele-specific transcriptional regulation of IRF4 in melanocytes is mediated by chromatin looping of the intronic rs12203592 enhancer to the IRF4 promoter. Hum. Molec. Genet. 24: 2649-2661, 2015. [PubMed: 25631878] [Full Text: https://doi.org/10.1093/hmg/ddv029]
Zheng, Y., Chaudhry, A., Kas, A., deRoos, P., Kim, J. M., Chu, T.-T., Corcoran, L., Treuting, P., Klein, U., Rudensky, A. Y. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses. Nature 458: 351-356, 2009. [PubMed: 19182775] [Full Text: https://doi.org/10.1038/nature07674]