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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 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 [dataset 3]

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.

2019-07-12 | GSE134206 | GEO

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

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 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 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 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

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

Synthetic ROR? agonists regulate multiple pathways to enhance antitumor immunity.

Project description:ROR?t is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are ROR?+ cells. To evaluate the role of ROR? in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate ROR? to a greater extent than the endogenous agonist desmosterol. These ROR? agonists enhance effector function of Type 17 cells by increasing the production of cytokines/chemokines such as IL-17A and GM-CSF, augmenting expression of co-stimulatory receptors like CD137, CD226, and improving survival and cytotoxic activity. ROR? agonists also attenuate immunosuppressive mechanisms by curtailing Treg formation, diminishing CD39 and CD73 expression, and decreasing levels of co-inhibitory receptors including PD-1 and TIGIT on tumor-reactive lymphocytes. The effects of ROR? agonists were not observed in ROR?-/- T cells, underscoring the selective on-target activity of the compounds. In vitro treatment of tumor-specific T cells with ROR? agonists, followed by adoptive transfer to tumor-bearing mice is highly effective at controlling tumor growth while improving T cell survival and maintaining enhanced IL-17A and reduced PD-1 in vivo. The in vitro effects of ROR? agonists translate into single agent, immune system-dependent, antitumor efficacy when compounds are administered orally in syngeneic tumor models. ROR? agonists integrate multiple antitumor mechanisms into a single therapeutic that both increases immune activation and decreases immune suppression resulting in robust inhibition of tumor growth. Thus, ROR? agonists represent a novel immunotherapy approach for cancer.

| S-EPMC5215247 | biostudies-literature

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