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Runx/CBFβ transcription factor complexes regulate Ccl5 expression through two novel enhancers to enhance tumor immunity

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE130600 | GEO | 2019/05/01

REPOSITORIES: GEO

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Similar Datasets

Runx/CBFβ transcription factor complexes regulate Ccl5 expression through two novel enhancers to enhance tumor immunity [dataset 2]

Project description:CCL5 (also known as RANTES) was originally known to be important to recruit memory T cells to infected sites, but it received much attention as an inhibitor to HIV’s entry into T lymphocytes of AIDS patients. Recently, it has been reported to be necessary to sustain Trm (Tissue-resident memory) T cells at local tissues as well as to play roles in manipulating tumor microenvironment by both host immunity and cancer cells. Nonetheless, little is known how Ccl5 expression is regulated, thus making it quite difficult for therapeutic intervention. Our study reveals that Runx/CBFβ transcription factor complexes antagonizes Ccl5 expression through two novel transcriptional enhancers. The proximal enhancer is required for the homeostatic expression of Ccl5 during the steady state, meanwhile the distal enhancer is necessary for the expression Ccl5 during the activated stage. We employed enChIP-seq to identify the distal enhancer located 1.35 Mb away from the promoter. This long distance interaction requires the help from Satb1, a global chromatin organizer. Our study reveals that the reduced amounts of Ccl5 by the deletion of the proximal enhancer results in an enhancement of metastasis in B16-F10 melanoma model. On the other hand, a Runx3-mutant mouse line in which Ccl5 expression is increased showed the opposite outcome, suggesting a novel inverse correlation between host Ccl5 levels and metastasis rate.

2019-05-01 | GSE130599 | GEO

Runx/CBFβ transcription factor complexes regulate Ccl5 expression through two novel enhancers to enhance tumor immunity [dataset 3]

2019-07-12 | GSE134206 | GEO

Runx/CBFβ transcription factor complexes regulate Ccl5 expression through two novel enhancers to enhance tumor immunity [dataset 1]

Project description:CCL5 (also known as RANTES) was originally known to be important to recruit memory T cells to infected sites, but it received much attention as an inhibitor to HIV’s entry into T lymphocytes of AIDS patients. Recently, it has been reported to be necessary to sustain Trm (Tissue-resident memory) T cells at local tissues as well as to play roles in manuplating tumor microenvironment by both host immunity and cancer cells. Nonetheless, little is known how Ccl5 expression is regulated, thus making it quite difficult for therapeutic intervention. Our study reveals that Runx/CBFβ transcription factor complexes antagonizes Ccl5 epxression through two novel transcriptional enhancers. The proximal enhancer is required for the homeostatic expression of Ccl5 during the steady state, meanwhile the distal enhancer is necessary for the expression Ccl5 during the activated stage. We employed enChIP-seq to identify the distal enhancer located 1.35 Mb away from the promoter. This long distance interaction requires the help from Satb1, a global chromatin organizer. Our study reveals that the redeced amounts of Ccl5 by the deletion of the proximal enhancer results in an enhancement of metastasis in B16-F10 melanoma model. On the other hand, a Runx3-mutant mouse line in which Ccl5 expression is increased showed the opposite outcome, suggesting a novel inverse correlation between host Ccl5 levels and metastasis rate.

2019-04-25 | GSE130235 | GEO

Runx/CBFβ transcription factor complexes regulate Ccl5 expression through two novel enhancers to enhance tumor immunity

Project description:Runx/CBFβ transcription factor complexes regulate Ccl5 expression through two novel enhancers to enhance tumor immunity

| PRJNA540714 | ENA

Runx/CBFβ transcription factor complexes regulate Ccl5 expression through two novel enhancers to enhance tumor immunity [dataset 3]

Project description:Runx/CBFβ transcription factor complexes regulate Ccl5 expression through two novel enhancers to enhance tumor immunity [dataset 3]

| PRJNA554314 | ENA

Runx/CBFβ transcription factor complexes regulate Ccl5 expression through two novel enhancers to enhance tumor immunity [dataset 1]

Project description:Runx/CBFβ transcription factor complexes regulate Ccl5 expression through two novel enhancers to enhance tumor immunity [dataset 1]

| PRJNA534422 | ENA

Runx/CBFβ transcription factor complexes regulate Ccl5 expression through two novel enhancers to enhance tumor immunity [dataset 2]

Project description:Runx/CBFβ transcription factor complexes regulate Ccl5 expression through two novel enhancers to enhance tumor immunity [dataset 2]

| PRJNA540715 | ENA

Runx-mediated regulation of CCL5 via antagonizing two enhancers influences immune cell function and anti-tumor immunity.

Project description:CCL5 is a unique chemokine with distinct stage and cell-type specificities for regulating inflammation, but how these specificities are achieved and how CCL5 modulates immune responses is not well understood. Here we identify two stage-specific enhancers: the proximal enhancer mediates the constitutive CCL5 expression during the steady state, while the distal enhancer located 1.35 Mb from the promoter induces CCL5 expression in activated cells. Both enhancers are antagonized by RUNX/CBFβ complexes, and SATB1 further mediates the long-distance interaction of the distal enhancer with the promoter. Deletion of the proximal enhancer decreases CCL5 expression and augments the cytotoxic activity of tissue-resident T and NK cells, which coincides with reduced melanoma metastasis in mouse models. By contrast, increased CCL5 expression resulting from RUNX3 mutation is associated with more tumor metastasis in the lung. Collectively, our results suggest that RUNX3-mediated CCL5 repression is critical for modulating anti-tumor immunity.

| S-EPMC7099032 | biostudies-literature

Small Molecule Inhibitor of CBFβ-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 CBFβ binding partner. CBFβ enhances DNA binding of RUNX subunits by relieving auto-inhibition. Both RUNX1 and CBFβ 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 CBFβ 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

Runx/Cbfβ complexes protect ILC2s from exhaustion during allergic airway inflammation

Project description:Group 2 innate lymphoid cells (ILC2s) have tissue-resident competence and contribute to the pathogenesis of allergic diseases. Therefore, there should be mechanisms to maintain the capacity of ILC2s to produce TH2 cytokines under chronic inflammatory conditions. Here, we report that Runx proteins are essential to prevent exaggerated activation of ILC2, in part by antagonizing GATA-3 function at steady state. However, during allergic inflammation, the absence of Runx in ILC2s impaired their ability to proliferate and produce effector TH2 cytokines and chemokines, but instead induced expression of T cell exhaustion markers including IL-10 and TIGIT. These exhausted ILC2s were unabale to induce type 2 immune responses against repeated allergen inhalation. Thus, Runx proteins protect ILC2s from exhaustion during continuous allergic inflammation.

2019-01-07 | GSE111871 | GEO

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