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HIF-1α and HIF-2α regulate overlapping and distinct transcriptional programs in primary human T cells [RNA-Seq]

ABSTRACT: Hypoxia-inducible factor 2α (HIF-2α) is a central oncogenic driver in clear cell renal cell carcinoma (ccRCC). Here, we investigated the cell-intrinsic effects of HIF-2α perturbation in primary human T cells. CRISPR/Cas9-mediated deletion of HIF-2α downregulated transcriptional programs associated with T cell effector function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324038 | GEO | 2026/04/01

REPOSITORIES: GEO

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	GSE324038_Project_Knm32.rsem_genes_expected_count.txt.gz	Txt
	GSE324038_Project_Knm32.rsem_genes_tpm.txt.gz	Txt

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HIF-1α and HIF-2α differently regulate tumour development, metabolism and inflammation of clear cell renal cell carcinoma in mice

Project description:Mutational inactivation of VHL is the earliest genetic event in the majority of ccRCCs, leading to activation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCCs and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Using an autochthonous ccRCC model, we show genetically that Hif1a is necessary for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are necessary for the clear cell phenotype. Transcriptomic and proteomic analyses revealed that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. Deficiency of HIF-2α increased CD8+ T cell infiltration and activation. These studies reveal different functions of HIF-1α and HIF-2α in ccRCC. SIGNIFICANCE The roles of HIF-1α and HIF-2α in ccRCC pathogenesis remain unclear. Using a mouse genetic approach we show that HIF-1α but not HIF-2α is important for tumour formation, contrary to predictions from studies of human ccRCC. We show that HIF-1α and HIF-2α transcriptionally regulate different aspects of metabolism and identify HIF-2α as a suppressor of immune cell infiltration and activation.

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Enhancer-Mediated Regulation of HIF-2α by the SOCS3–JAK1–STAT3 Axis in Renal Cancer

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