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

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

PROVIDER: PRJNA672951 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12925912_1.fastq.gz	Fastqsanger.gz
	SRR12925912_2.fastq.gz	Fastqsanger.gz
	SRR12925913_1.fastq.gz	Fastqsanger.gz
	SRR12925913_2.fastq.gz	Fastqsanger.gz
	SRR12925914_1.fastq.gz	Fastqsanger.gz

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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.

2020-10-29 | GSE160327 | GEO

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

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.

2024-05-23 | GSE243058 | GEO

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

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

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

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RORa enforces stability of the T-helper-17 cell effector program (ChIP-Seq)

Project description:Chronic inflammation is responsible for a number of debilitating human diseases including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. The Th17 subset of T lymphocytes is an important player in the development of these pathogenic conditions. The transcription factor, RORgt was initially coined the master regulator of the Th17 program, but targeting RORgt therapeutically is dangerous owing to an enhanced risk of thymoma upon its inhibition. Another ROR family member, RORa, has also been implicated in Th17 function.

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RORa enforces stability of the T-helper-17 cell effector program (RNA-Seq)

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RORa enforces stability of the T-helper-17 cell effector program (ATAC-Seq)

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RORa enforces stability of the T-helper-17 cell effector program (ChIP-Seq (2))

2022-10-25 | GSE163341 | GEO

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

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

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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]