TEAD1 condensates are transcriptionally inactive storage sites on the pericentromeric heterochromatin in cancer cells

TEA domain transcription factor 1 (TEAD1), a Hippo pathway transcription factor important in cellular homeostasis and development, is increasingly implicated in cancer biology. Here we reveal an unexpected role for TEAD1 in organizing nuclear condensates, independent of active transcription. Using high-resolution imaging, ChIP–seq, RNA sequencing and proximity-based proteomics, we demonstrate that in patient-derived renal cell carcinoma cells, TEAD1 forms micrometre-sized condensates by binding to heterochromatic pericentromeric regions using its DNA-binding domain. TEAD-specific MCAT motifs selectively enrich and cluster in the pericentromeric region to specifically seed TEAD1 condensates. TEAD1 condensates do not activate transcription but instead serve as depots for excess TEAD1, and disruption of TEAD1 condensates leads to increases in YAP and TEAD target gene expression. This organization of TEAD1 contrasts with that observed in other genomic regions of both renal cell carcinoma and normal kidney cells, in which TEAD1 associates with markers of active transcription. Our findings provide a mechanistic framework for the dual regulatory roles of TEAD1 and offer new insights into its contribution to transcriptional dysregulation and tumour progression. Wang, Liang and colleagues show that the TEAD1 transcription factor can organize micrometre-sized nuclear biomolecular condensates independently of active transcription. TEAD1 condensates may act as depots for excess TEAD1.