Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation
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ABSTRACT:
PROVIDER: PRJNA732918 | ENA |
REPOSITORIES: ENA
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Project description:Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early-onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics including fevers and ulcers that responded to IL-1, TNF, or IL-12p40 blockade. Using cells from patients and two newly generated mouse models, we uncovered hyperinflammatory responses of ELF4-mutant macrophages to a range of innate stimuli. Mechanistically, Elf4 in macrophages both sustained expression of anti-inflammatory genes such as Il1rn and limited upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1, and neutrophil chemoattractants. Indeed, therapeutic Trem1 blockade reversed inflammation and intestine pathology in Elf4-mutant mice challenged with lipopolysaccharide in vivo. Thus, the ELF4 transcription factor restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory diseases such as IBD.
2021-07-29 | GSE175569 | GEO
Project description:To elucidate how ELF4 confers anti-growth activity, gene expression profiles were compared between wildtype- and mutant-expressing T3M-1 Cl-10 cells with the use of DNA microarrays. T3M-1 Cl-10 cells were infected with a mock retrovirus or virus generated from pMXS-ires-EGFP expressing ELF4 or ELF4(L211M), and EGFP?positive fractions were purified with a cell sorter. Thus gene expression profiling of purely mock/ELF4/ELF4(L211M)-expressing cells was performed with SurePrint G3 Human Gene Expression 8×60K v2 Microarray.
2013-12-04 | E-GEOD-52855 | biostudies-arrayexpress
Project description:ELF4 (also known as MEF) is a member of the ETS family of transcriptional factors. While an oncogenic role has been demonstrated for ELF4 mainly in hematopoietic malignancies, its definitive function in human carcinogenesis is not clear yet. Here we demonstrate that a wide array of human tumors carry somatic, loss-of-function mutations in ELF4 for its transcriptional activity, and restoring its function exerts anti-proliferative effects. To further explore the tumor suppressive function of ELF4, its binding sites were searched among the human genome with the use of chromatin immunoprecipitation coupled with sequencing (ChIP-seq). Examination of binding site for FLAG-immunoprecipitated mock, ELF4 (WT) and ELF4 (L211M) with each input sample as a control.
2016-03-01 | E-GEOD-53357 | biostudies-arrayexpress
Project description:STING transmits signals downstream of the cytosolic DNA sensor cGAS, leading to transcriptional up-regulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (SAVI) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi. Since pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.
2024-12-31 | GSE283416 | GEO
Project description:STING transmits signals downstream of the cytosolic DNA sensor cGAS, leading to transcriptional up-regulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (SAVI) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi. Since pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.
2024-12-31 | GSE283415 | GEO
Project description:ELF4 (also known as MEF) is a member of the ETS family of transcriptional factors. While an oncogenic role has been demonstrated for ELF4 mainly in hematopoietic malignancies, its definitive function in human carcinogenesis is not clear yet. Here we demonstrate that a wide array of human tumors carry somatic, loss-of-function mutations in ELF4 for its transcriptional activity, and restoring its function exerts anti-proliferative effects. To further explore the tumor suppressive function of ELF4, its binding sites were searched among the human genome with the use of chromatin immunoprecipitation coupled with sequencing (ChIP-seq).
2016-03-01 | GSE53357 | GEO
Project description:Host defense and inflammation are regulated by the NF-kB essential modulator (NEMO), a scaffolding protein with a broad immune cell and tissue expression profile. Hypomorphic mutations in inhibitor of nuclear factor kappa B kinase regulatory subunit gamma (IKBKG) encoding NEMO typically present with immunodeficiency. Here we characterized a novel pediatric autoinflammatory syndrome in 3 unrelated male patients with distinct X-linked IKBKG germ-line mutations that led to overexpression of a NEMO protein isoform lacking the domain encoded by exon 5 (NEMO-Dex5). This isoform failed to associate with TANK binding kinase 1 (TBK1), and dermal fibroblasts from affected patients activated NF-kB in response to TNF, but not TLR3 or RIG-I-like-receptor (RLR) stimulation when isoform levels were high. By contrast, T cells, monocytes and macrophages that expressed NEMO-Dex5 exhibited increased NF-kB activation and IFN production, and blood cells from these patients expressed a strong interferon and NF-kB transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi) that was stabilized by NEMO-Dex5, promoting type I IFN induction and antiviral responses. These data reveal how IKBKG mutations that lead to alternative splicing of skipping exon 5 cause a clinical phenotype we name NEMO Deleted exon 5 Autoinflammatory Syndrome (NDAS), distinct from the immunodeficiency syndrome resulting from loss-of-function IKBKG mutations.
2023-05-17 | GSE196243 | GEO
Project description:To elucidate how ELF4 confers anti-growth activity, gene expression profiles were compared between wildtype- and mutant-expressing T3M-1 Cl-10 cells with the use of DNA microarrays.
2013-12-04 | GSE52855 | GEO
Project description:ELF4 is a transcription factor, and to identify its potential targets, the inflamed colons of wild type and Elf4 deficient mice were subjected to whole genome RNA sequencing.
2019-10-16 | GSE121305 | GEO
Project description:Transcription factors that regulate quiescence, proliferation, and homing of lymphocytes are critical for effective immune system function. In the present study, we demonstrated that the transcription factor ELF4 directly activates the tumor suppressor KLF4 downstream of T cell receptor (TCR) signaling to induce cell cycle arrest in naïve CD8+ T cells. Elf4- and Klf4-deficient mice accumulated CD8+CD44hi T cells during steady-state conditions and generated more memory T cells after immunization. The homeostatic expansion of CD8+CD44hi T cells in Elf4-null mice resulted in a redistribution of cells to non-lymphoid tissue due to reduced expression of the transcription factor KLF2, and the surface proteins CCR7 and CD62L. This work describes the combinatorial role of lymphocyte-intrinsic factors in the control of T cell homeostasis, activation and homing.
2009-03-24 | GSE15324 | GEO