Speckles are nuclear structures thought to amplify expression of select stress-responsive genes. Although speckle-resident proteins are altered in cancer, their functional relevance remained elusive. Alexander et al. now show that speckle phenotypes correlate with patient survival in clear cell renal cell carcinoma (ccRCC) and identify that HIF2α regulates speckle–DNA associations, fine-tuning the expression of select HIF2α target genes.

In a ccRCC cell line, the authors first show that HIF2α, which is a highly active transcription factor in ccRCC, regulates speckle–DNA association. Pharmacological inhibition of the HIF2α–DNA interaction in cells diminished gene–speckle association in regions that often corresponded to HIF2α-responsive genes.