Abstract
Activation of cellular hypoxia pathways, orchestrated by HIF (hypoxia-inducible factor) transcription factors, is a common feature of multiple tumor types, resulting from microenvironment factors and oncogenic mutation. Although they help drive many of the “hallmarks” of cancer and are associated with poor outcome and resistance to therapy, the transcriptional targets of HIF vary considerably depending on the cell type. By integrating 72 genome-wide assays of HIF binding and transcriptional regulation from multiple cancer types, we define a consensus set of 48 HIF target genes that is highly conserved across cancer types and cell lineages. These genes provide an effective marker of HIF activation in bulk and single-cell transcriptomic analyses across a wide range of cancer types and in malignant and stromal cell types. This allows the tissue-orchestrated responses to the hypoxic tumor microenvironment and to oncogenic HIF activation to be deconvoluted at the tumor and single-cell level.
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•ChIP-seq and RNA-seq datasets are used to identify HIF target genes in multiple cancers•Consensus HIF target genes are used as a pan-cancer HIF metagene•The HIF metagene can be used as an endogenous marker of HIF activity/hypoxia•The HIF metagene allows analysis of tumor samples via bulk and single-cell datasets
Lombardi et al. define a consensus set of HIF target genes using 72 ChIP-seq and RNA-seq datasets and use this as an “HIF metagene” to detect HIF activation/hypoxia in clinical samples. This enables investigation of tumor- and cell-type-specific responses to HIF in bulk and single-cell RNA-seq datasets.