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RORA proximal enhancer regulates its expression during early human Th17 cell differentiation

ABSTRACT: RORA proximal enhancer regulates its expression during early human Th17 cell differentiation

PROVIDER: PRJNA1016309 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26049700_1.fastq.gz	Fastqsanger.gz
	SRR26049700_2.fastq.gz	Fastqsanger.gz
	SRR26049800_1.fastq.gz	Fastqsanger.gz
	SRR26049800_2.fastq.gz	Fastqsanger.gz
	SRR26049701_1.fastq.gz	Fastqsanger.gz

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RORA proximal enhancer regulates its expression during early human Th17 cell differentiation [ChIP]

Project description:Distal regulatory elements, such as enhancers, play a pivotal role in dictating cell identity by controlling the transcriptional status of specific cells. The comprehensive understanding of the epigenetic landscape, encompassing enhancer establishment and chromatin accessibility, during the differentiation of human Th17 cells remains incomplete. Leveraging ATAC-seq based chromatin accessibility profile along with the profiling of key histone marks we identified potential enhancers crucial for fate specification of Th17 cells. We found that 24 single nucleotide polymorphisms (SNPs) associated with autoimmune diseases were located near Th17-enhancers. Interestingly, these SNPs overlapped the binding sites of transcription factor active in Th17 cells. Among the Th17 specific enhancers, we identified an enhancer in the intron of RAR-related orphan receptor alpha (RORA) that was earlier predicted to regulate RORA expression. Functional validation through luciferase reporter assays confirmed that this enhancer positively regulate the transcription. Moreover, employing CRISPR-Cas9-mediated deletion of a transcription factor binding site-rich region within the identified RORA enhancer, we demonstrated its role in regulating RORA transcription. These findings provide insights into the potential mechanism by which the RORA enhancer modulates Th17 differentiation and into the role of regulatory SNPs within noncoding regions in conferring resistance or susceptibility to Th17 cell-mediated autoimmune pathologies.

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RORA proximal enhancer regulates its expression during early human Th17 cell differentiation [ATAC]

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RORA proximal enhancer regulates its expression during early human Th17 cell differentiation [ATAC]

Project description:RORA proximal enhancer regulates its expression during early human Th17 cell differentiation [ATAC]

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Genetic and pharmacological inhibition of the nuclear receptor RORa regulates Th17 driven inflammatory disorders

Project description:Full development of IL-17 producing CD4+ T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORa and RORgt. Despite this evidence, RORa is considered functionally redundant to RORgt; thus, the function and therapeutic value of RORa in TH17 cells remains underexplored. Using mouse models of autoimmune and chronic inflammation, we show that expression of RORa is required for TH17 cell pathogenicity. T-cell specific deletion of RORa reduced the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation was associated with decreased TH17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3+ T regulatory (Treg) cells. Importantly, inhibition of RORa with a selective small molecule antagonist largely phenocopied our genetic data, potently suppressing the in vivo development of both chronic/progressive and relapsing/remitting EAE but had no effect on overall thymic cellularity. Furthermore, use of the RORa antagonist effectively inhibited human TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORa acts independently of RORgt in programming TH17 pathogenicity and identifies RORa as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity.

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RORA proximal enhancer regulates its expression during early human Th17 cell differentiation

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CIP2A negatively regulates Th17 differentiation

Project description:Interleukin 17 (IL-17) producing T helper 17 (Th17) cells are critical drivers of pathogenesis in a variety of autoimmune and inflammatory diseases. Strategies to mitigate excessive Th17 response thus remain an attractive target for immunotherapies. Here we report that Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) regulates IL-17 production by Th17 cells in human and mouse. Using CIP2A knock-out (KO) mice and siRNA-mediated CIP2A silencing in human primary CD4+ T cells, we demonstrated that CIP2A silencing results in a significant increase in IL-17 production. Interestingly, CIP2A deficient Th17 cells were characterized by increased strength and duration of STAT3 (Y705) phosphorylation. Genome-wide gene expression profile as well as the p-STAT3 (Y705) interactome of CIP2A deficient Th17 cells identified that CIP2A regulates the strength of the interaction between Acylglycerol kinase (AGK) and STAT3, and thereby, modulates STAT3 phosphorylation as well as expression of IL-17 in Th17 cells. Our results uncover the physiological function of CIP2A in Th17 cells and provides new opportunities for therapeutic intervention in Th17 cell mediated diseases.

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