Runx/Cbfβ complexes protect ILC2s from exhaustion during allergic airway inflammation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA438449 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6840680.fastq.gz | Fastqsanger.gz | |||
| SRR6840681.fastq.gz | Fastqsanger.gz | |||
| SRR6840682.fastq.gz | Fastqsanger.gz | |||
| SRR6840673.fastq.gz | Fastqsanger.gz | |||
| SRR6840683.fastq.gz | Fastqsanger.gz |
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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.
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Project description:ILC2s regulate type2 immune responses and protect against helminth infection. We found that ILC2s can be expanded in the presence of a combination of cytokines IL-2 and IL-1b. To better understand the functional and phenotypic consequence of IL-1β activation of ILC2s, we utilized whole transcriptome sequencing (RNA-seq) of freshly isolated ILC2s and IL-1β-primed ILC2s. Differential expression analysis revealed a substantial number of genes underwent significant change between the two conditions (total 4,744 gene, FDR<0.01, Fold change >2), among which 3,871 genes were upregulated in IL-1β –primed ILC2s.
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Project description:Group 2 innate lymphoid (ILC2) cells are major producers of the cytokines that drive allergic asthma and elevated levels of ILC2s have been detected in the blood and sputum of asthma patients. Asthma susceptibility has strong (epi)genetic components, but the underlying mechanisms and whether they are linked to ILC2 biology remain unclear. To reveal the molecular basis of ILC2 function in allergic airway inflammation (AAI) and assess its relevance for understanding how genetic variation affects asthma susceptibility. Gata3-IRES-YFP reporter mice were used to isolate ILC2s from bronchoalveolar lavage fluid and lymph nodes. Human naive ILC2s were purified from peripheral blood and activated in vitro. We employed RNA-Seq, ChIPm-Seq and computational approaches to study the transcriptome and epigenome in the context of ILC2 activation, tissue-specific functions and genetic susceptibility to asthma. Activated ILC2s displayed a tissue-specific gene expression signature that emerged from a highly similar epigenome. We identify superenhancers - a class of regulatory regions susceptible to epigenetic drugs - controlling ILC2 identity and asthma-associated genes. The majority of genes implicated in asthma by genome-wide association studies resided in an active or primed state in ILC2s. A substantial number of asthma-associated genetic variants were found in ILC2 gene regulatory elements. Our genome-wide analyses reveal new potential functions for ILC2s in AAI, which possess a plastic and flexible epigenome. Importantly, we reveal a strong link between gene regulatory mechanisms in ILC2s and the (epi)genetic basis of asthma susceptibility, supporting a pathogenic role for ILC2s in human asthma.
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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
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
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.
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Project description:Runx/CBFβ transcription factor complexes regulate Ccl5 expression through two novel enhancers to enhance tumor immunity
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Project description:Group 2 innate lymphoid cells (ILC2s) in the lung are stimulated by inhaled allergens. ILC2s do not directly recognize allergens but they are stimulated by cytokines including interleukin (IL)-33 released by damaged epithelium.Lung ILC2s, upon stimulation, produce T helper 2 cell-type cytokines inducing T cell independent allergic lung inflammation. We now report that lung ILC2s, upon activation by an allergen or IL-33, acquire the properties of memory cells. The activated ILC2s initially proliferate and secrete cytokines, followed by a contraction phase as they stop producing cytokines. Nevertheless, some persist long after the resolution of the inflammation and acquire intrinsic capacities to react to unrelated allergens more vigorously than naïve ILC2s, thus mediating a severe allergic lung inflammation. Gene expression profiles of the previously activated ILC2s show a gene signature of memory T cells. These antigen non-specific memory ILC2s may explain why asthma patients are often sensitized to multiple allergens. ILC2s were isolated from mouse lungs from naive and IL-33 injected mice 4 days, 14 days and 4 months after the initial treatment. RNA was extracted from those ILC2 populations and analyzed for gene expression profiles. RNA was also extracted from ILC2s isolated from lung draining mediastinal lymph node (mLN) 4 days and 14 days after IL-33 treatment.
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Project description:As the most common degenerative joint disease, osteoarthritis (OA) contributes significantly to pain and disability during aging. Several genes of interest involved in articular cartilage damage in OA have been identified. However, the direct causes of OA are poorly understood. Evaluating the public human RNA-seq dataset showed that Cbfβ, (subunit of a heterodimeric Cbfβ/Runx1,Runx2, or Runx3 complex) expression is decreased in the cartilage of patients with OA. Here, we found that the chondrocyte-specific deletion of Cbfβ in tamoxifen-induced Cbfβf/fCol2α1-CreERT mice caused a spontaneous OA phenotype, worn articular cartilage, increased inflammation, and osteophytes. RNA-sequencing analysis showed that Cbfβ deficiency in articular cartilage resulted in reduced cartilage regeneration, increased canonical Wnt signaling and inflammatory response, and decreased Hippo/YAP signaling and TGF-β signaling. Immunostaining and western blot validated these RNA-seq analysis results. ACLT surgery-induced OA decreased Cbfβ and Yap expression and increased active β-catenin expression in articular cartilage, while local AAV-mediated Cbfβ overexpression promoted Yap expression and diminished active β-catenin expression in OA lesions. Remarkably, AAV-mediated Cbfβ overexpression in knee joints of mice with OA showed the significant protective effect of Cbfβ on articular cartilage in the ACLT OA mouse model. Overall, this study, using loss-of-function and gain-of-function approaches, uncovered that low expression of Cbfβ may be the cause of OA. Moreover, Local admission of Cbfβ may rescue and protect OA through decreasing Wnt/β-catenin signaling, and increasing Hippo/Yap signaling and TGFβ/Smad2/3 signaling in OA articular cartilage, indicating that local Cbfβ overexpression could be an effective strategy for treatment of OA. Using unbiased genome-wide RNA-seq data from Cbfβf/f;Col2α1-Cre hip joint articular cartilage and Cbfβf/f;Aggrecan-cre knee joint articular cartilage and their controls, we examined Cbfβ-mediated transcriptional targets for articular cartilage regeneration in OA.
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