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.
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.
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.
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.
Project description:Prior studies by our group demonstrated the essential role of core-binding factor subunit β (CBFβ) in prepubertal male germline development. CBFβ is a common co-factor to the runt-related family of transcription factors (RUNX), of which RUNX1 and RUNX3 are expressed in prepubertal germ cells. Therefore, to gain insights into the functional roles of CBFβ and RUNX proteins in the male germline, we conducted cleavage under targets & release using nuclease (CUT&RUN) for CBFβ, RUNX1, and RUNX3 within male germ cells. Collectively, our analyses revealed both unique and overlapping genomic localizations of CBFβ and RUNX1/3 in male germ cells.