Inherent single-cell heterogeneity of the transcriptional response to hypoxia in cancer cells

Hypoxia-inducible factor (HIF) is a master regulator of cancer cell adaptation to tumor hypoxia and is involved in cancer progression. Single-cell (sc) differences in the HIF response allow for tumor evolution and cause therapy resistance. These sc-differences are usually ascribed to tumor microenvironmental differences and/or clonal (epi)genetic variability. However, the sc-heterogeneity of the HIF response in otherwise identical cells cultured under defined in vitro conditions has not yet been addressed. Therefore, we analyzed the sc-response to hypoxia in nonclonal cell lines and multiple clonal derivatives, including HIF-1a or HIF-2a knockouts. While HIF-1a and HIF-1 target mRNA sc-heterogeneity was slightly higher than global transcription or specific housekeeping mRNAs, HIF-2a and especially HIF-2 target mRNA sc-heterogeneity was extraordinary, and remained in independent clones and following HIFa knockouts. Unexpectedly, neither HIF-2a mRNA nor nuclear protein levels correlated w..., , # Data from: Inherent single-cell heterogeneity of the transcriptional response to hypoxia in cancer cells

Dataset DOI: [10.5061/dryad.z08kprrr3](10.5061/dryad.z08kprrr3)

**Description of the data and file structure**

Underlying primary data for the publication Wilk et al., \"Inherent single-cell heterogeneity of the transcriptional response to hypoxia in cancer cells\" in NAR Cancer, 2025, 7, zcaf021. All information about data content and file structure can be found therein.

**Files and variables**

**File: Wilk_Figures.zip, PythonScript_DensityPlots.ipynb, and PythonScript_HeterogeneityPlots.ipynb**

**Description:** Underlying primary data of Figures 1 to 6 of the publication Wilk et al., \"Inherent single-cell heterogeneity of the transcriptional response to hypoxia in cancer cells\".

**Code/software**

Image viewer, Excel, cell profiler, Adobe acrobat, Python script (ipynb).
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