{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE307nnn/GSE307907/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE307907"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"A Human RORγt Mutant Enhances Th17-Mediated Inflammation via Increased HIF-1α Recruitment","description":"T helper 17 (Th17) cells play a central role in mucosal defense and autoimmune pathology, with their differentiation and effector function critically controlled by the transcription factor RORγt. While genome-wide association studies (GWAS) have identified variants in the RORC locus associated with inflammatory diseases, the functional impact of these variants remains largely unexplored. Here, we report the identification and characterization of a hyperactive RORγt point mutation, N277D (mouse homolog N275D), which enhances Th17 inflammatory potential through increased cooperation with the hypoxia-inducible factor HIF-1α. Using a combination of computational modeling, retroviral expression, and CRISPR-engineered knock-in mice, we demonstrate that RORγtN275D promotes IL-17A⁺IFN-γ⁺ Th17 cell differentiation and exacerbates colitis in a T cell transfer model without affecting T cell development or homeostasis. Transcriptomic and metabolomic profiling revealed upregulation of glycolytic and hypoxia-associated pathways in mutant Th17 cells. Consistent with enhanced RORγtN275D-HIF-1α interaction, RORγtN275D was recruited to HIF-1α binding site at the Pdk1 locus, which is required for the upregulation of IFN-γ production in mutant Th17 cells. These findings reveal a novel regulatory axis between RORγt and HIF-1α that links transcriptional and metabolic programming in pathogenic Th17 cells and suggest a framework for functionally interrogating autoimmune risk variants to uncover therapeutic targets.","dates":{"publication":"2026/02/16"},"accession":"GSE307907","cross_references":{"GSM":["GSM9233791","GSM9233790","GSM9233793","GSM9233792","GSM9233795","GSM9233794"],"GPL":["34290"],"GSE":["307907"],"taxon":["Mus musculus"],"PMID":["[41849346]"]}}