Browse
Submit Data
Databases
API
Help

Dataset Information

19 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Runx Transcription Factors in T Cells-What Is Beyond Thymic Development?

ABSTRACT: Runx proteins (also known as Runt-domain transcription factors) have been studied for a long time as key regulators of cellular differentiation. RUNX2 has been described as essential for osteogenesis, whereas RUNX1 and RUNX3 are known to control blood cell development during different stages of cell lineage specification. However, recent studies show evidence of complex relationships between RUNX proteins, chromatin-modifying machinery, the cytoskeleton and different transcription factors in various non-embryonic contexts, including mature T cell homeostasis, inflammation and cancer. In this review, we discuss the diversity of Runx functions in mature T helper cells, such as production of cytokines and chemokines by different CD4 T cell populations; apoptosis; and immunologic memory acquisition. We then briefly cover recent findings about the contribution of RUNX1, RUNX2 and RUNX3 to various immunologic diseases. Finally, we discuss areas that require further study to better understand the role that Runx proteins play in inflammation and immunity.

SUBMITTER: Korinfskaya S

PROVIDER: S-EPMC8377396 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Thymic epithelial cells co-opt lineage-defining transcription factors to eliminate autoreactive T cells.

Project description:Medullary thymic epithelial cells (mTECs) ectopically express thousands of peripheral-tissue antigens (PTAs), which drive deletion or phenotypic diversion of self-reactive immature T cells during thymic differentiation. Failure of PTA expression causes multiorgan autoimmunity. By assaying chromatin accessibility in individual mTECs, we uncovered signatures of lineage-defining transcription factors (TFs) for skin, lung, liver, and intestinal cells-including Grhl, FoxA, FoxJ1, Hnf4, Sox8, and SpiB-in distinct mTEC subtypes. Transcriptomic and histologic analyses showed that these subtypes, which we collectively term mimetic cells, expressed PTAs in a biologically logical fashion, mirroring extra-thymic cell types while maintaining mTEC identity. Lineage-defining TFs bound to mimetic-cell open chromatin regions and were required for mimetic cell accumulation, whereas the tolerogenic factor Aire was partially and variably required. Expression of a model antigen in mimetic cells sufficed to induce cognate T cell tolerance. Thus, mTECs co-opt lineage-defining TFs to drive mimetic cell accumulation, PTA expression, and self-tolerance.

| S-EPMC9469465 | biostudies-literature

The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells.

Project description:Members of the Runx family of transcriptional regulators are required for the appropriate expression of CD4 and CD8 at discrete stages of T cell development. The roles of these factors in other aspects of T cell development are unknown. We used a strategy to conditionally inactivate the genes encoding Runx1 or Runx3 at different stages of thymocyte development, demonstrating that Runx1 regulates the transitions of developing thymocytes from the CD4(-)CD8(-) double-negative stage to the CD4(+)CD8(+) double-positive (DP) stage and from the DP stage to the mature single-positive stage. Runx1 and Runx3 deficiencies caused marked reductions in mature thymocytes and T cells of the CD4(+) helper and CD8(+) cytotoxic T cell lineages, respectively. Runx1-deficient CD4(+) T cells had markedly reduced expression of the interleukin 7 receptor and exhibited shorter survival. In addition, inactivation of both Runx1 and Runx3 at the DP stages resulted in a severe block in development of CD8(+) mature thymocytes. These results indicate that Runx proteins have important roles at multiple stages of T cell development and in the homeostasis of mature T cells.

| S-EPMC2118679 | biostudies-literature

RUNX transcription factors: association with pediatric asthma and modulated by maternal smoking.

Project description:Intrauterine smoke exposure (IUS) is a strong risk factor for development of airways responsiveness and asthma in childhood. Runt-related transcription factors (RUNX1-3) have critical roles in immune system development and function. We hypothesized that genetic variations in RUNX1 would be associated with airway responsiveness in asthmatic children and that this association would be modified by IUS. Family-based association testing analysis in the Childhood Asthma Management Program genome-wide genotype data showed that 17 of 100 RUNX1 single-nucleotide polymorphisms (SNPs) were significantly (P < 0.03-0.04) associated with methacholine responsiveness. The association between methacholine responsiveness and one of the SNPs was significantly modified by a history of IUS exposure. Quantitative PCR analysis of immature human lung tissue with and without IUS suggested that IUS increased RUNX1 expression at the pseudoglandular stage of lung development. We examined these associations by subjecting murine neonatal lung tissue with and without IUS to quantitative PCR (N = 4-14 per group). Our murine model showed that IUS decreased RUNX expression at postnatal days (P)3 and P5 (P < 0.05). We conclude that 1) SNPs in RUNX1 are associated with airway responsiveness in asthmatic children and these associations are modified by IUS exposure, 2) IUS tended to increase the expression of RUNX1 in early human development, and 3) a murine IUS model showed that the effects of developmental cigarette smoke exposure persisted for at least 2 wk after birth. We speculate that IUS exposure-altered expression of RUNX transcription factors increases the risk of asthma in children with IUS exposure.

| S-EPMC3213989 | biostudies-literature

Core-binding factor ? and Runx transcription factors promote adaptive natural killer cell responses.

Project description:Natural killer (NK) cells are innate lymphocytes that have features of adaptive immunity such as clonal expansion and generation of long-lived memory. Interleukin-12 (IL-12) signaling through its downstream transcription factor signal transducer and activator of transcription 4 (STAT4) is required for the generation of memory NK cells after expansion. We identify gene loci that are highly enriched for STAT4 binding using chromatin immunoprecipitation sequencing for STAT4 and the permissive histone mark H3K4me3 in activated NK cells. We found that promoter regions of Runx1 and Runx3 are targets of STAT4 and that STAT4 binding during NK cell activation induces epigenetic modifications of Runx gene loci resulting in increased expression. Furthermore, specific ablation of Runx1, Runx3, or their binding partner Cbfb in NK cells resulted in defective clonal expansion and memory formation during viral infection, with evidence for Runx1-mediated control of a cell cycle program. Thus, our study reveals a mechanism whereby STAT4-mediated epigenetic control of individual Runx transcription factors promotes the adaptive behavior of antiviral NK cells.

| S-EPMC6265048 | biostudies-literature

Small Molecule Inhibitor of CBF?-RUNX Binding for RUNX Transcription Factor Driven Cancers.

Project description:Transcription factors have traditionally been viewed with skepticism as viable drug targets, but they offer the potential for completely novel mechanisms of action that could more effectively address the stem cell like properties, such as self-renewal and chemo-resistance, that lead to the failure of traditional chemotherapy approaches. Core binding factor is a heterodimeric transcription factor comprised of one of 3 RUNX proteins (RUNX1-3) and a CBF? binding partner. CBF? enhances DNA binding of RUNX subunits by relieving auto-inhibition. Both RUNX1 and CBF? are frequently mutated in human leukemia. More recently, RUNX proteins have been shown to be key players in epithelial cancers, suggesting the targeting of this pathway could have broad utility. In order to test this, we developed small molecules which bind to CBF? and inhibit its binding to RUNX. Treatment with these inhibitors reduces binding of RUNX1 to target genes, alters the expression of RUNX1 target genes, and impacts cell survival and differentiation. These inhibitors show efficacy against leukemia cells as well as basal-like (triple-negative) breast cancer cells. These inhibitors provide effective tools to probe the utility of targeting RUNX transcription factor function in other cancers.

| S-EPMC4919611 | biostudies-literature

The transcription factors T-bet and Runx are required for the ontogeny of pathogenic interferon-?-producing T helper 17 cells.

Project description:T helper 17 (Th17) cells can give rise to interleukin-17A (IL-17A)- and interferon (IFN)-?-double-producing cells that are implicated in development of autoimmune diseases. However, the molecular mechanisms that govern generation of IFN-?-producing Th17 cells are unclear. We found that coexpression of the Th1 and Th17 cell master transcription factors, T-bet and retinoid-related orphan receptor gamma-t (ROR?t), respectively, did not generate Th cells with robust IL-17 and IFN-? expression. Instead, development of IFN-?-producing Th17 cells required T-bet and Runx1 or Runx3. IL-12-stimulated Th17 cells upregulated Runx1, which bound to the Ifng locus in a T-bet-dependent manner. Reciprocally, T-bet or Runx1 deficiency or inhibition of Runx transcriptional activity impaired the development of IFN-?-producing Th17 cells during experimental autoimmune encephalomyelitis, which correlated with substantially ameliorated disease course. Thus, our studies identify a critical role for T-bet and Runx transcription factors in the generation of pathogenic IFN-?-producing Th17 cells.

| S-EPMC3965587 | biostudies-literature

Thymic mimetic cells function beyond self-tolerance

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-08-27 | GSE236075 | GEO

Beyond Transcription: Roles of Transcription Factors in Pre-mRNA Splicing.

Project description:Whereas individual steps of protein-coding gene expression in eukaryotes can be studied in isolation in vitro, it has become clear that these steps are intimately connected within cells. Connections not only ensure quality control but also fine-tune the gene expression process, which must adapt to environmental changes while remaining robust. In this review, we systematically present proven and potential mechanisms by which sequence-specific DNA-binding transcription factors can alter gene expression beyond transcription initiation and regulate pre-mRNA splicing, and thereby mRNA isoform production, by (i) influencing transcription elongation rates, (ii) binding to pre-mRNA to recruit splicing factors, and/or (iii) blocking the association of splicing factors with pre-mRNA. We propose various mechanistic models throughout the review, in some cases without explicit supportive evidence, in hopes of providing fertile ground for future studies.

| S-EPMC6734189 | biostudies-literature

The evolutionary origin of the Runx/CBFbeta transcription factors--studies of the most basal metazoans.

Project description:BACKGROUND:Members of the Runx family of transcriptional regulators, which bind DNA as heterodimers with CBFbeta, are known to play critical roles in embryonic development in many triploblastic animals such as mammals and insects. They are known to regulate basic developmental processes such as cell fate determination and cellular potency in multiple stem-cell types, including the sensory nerve cell progenitors of ganglia in mammals. RESULTS:In this study, we detect and characterize the hitherto unexplored Runx/CBFbeta genes of cnidarians and sponges, two basal animal lineages that are well known for their extensive regenerative capacity. Comparative structural modeling indicates that the Runx-CBFbeta-DNA complex from most cnidarians and sponges is highly similar to that found in humans, with changes in the residues involved in Runx-CBFbeta dimerization in either of the proteins mirrored by compensatory changes in the binding partner. In situ hybridization studies reveal that Nematostella Runx and CBFbeta are expressed predominantly in small isolated foci at the base of the ectoderm of the tentacles in adult animals, possibly representing neurons or their progenitors. CONCLUSION:These results reveal that Runx and CBFbeta likely functioned together to regulate transcription in the common ancestor of all metazoans, and the structure of the Runx-CBFbeta-DNA complex has remained extremely conserved since the human-sponge divergence. The expression data suggest a hypothesis that these genes may have played a role in nerve cell differentiation or maintenance in the common ancestor of cnidarians and bilaterians.

| S-EPMC2527000 | biostudies-literature

Thymic mimetic cells function beyond self-tolerance [Spib]

Project description:To examine the Microfold thymic epithelial cell transcriptome within the mTEC-III compartment we sorted this population from young Spib KO mice and performed bulk RNAseq

2023-08-28 | GSE236074 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data