The transcription factor TEAD1 forms repressive biomolecular condensates in renal cell carcinomas

The chromatin adaptor protein YAP1 is an important regulator of transcriptional activation and chromatin architecture in response to Hippo pathway signaling. YAP1 binds TEAD-family transcription factors and forms phase-separated biomolecular condensates, specifically transcriptional hubs, in response to hyperosmolarity and other cellular and environmental cues. In Renal Cell Carcinoma (RCC), a particularly lethal form of kidney cancer with poor treatment options, YAP1 and its transcription factor partner TEAD1 are often up-regulated and indicate poor prognosis. We have found that in certain patient-derived RCC cell lines with high levels of YAP1 and TEAD1 expression, TEAD1 forms atypical large nuclear foci, distinct from normal kidney cells and other subtypes of RCC. These few large TEAD1 foci are co-occupant with the repressive histone mark H3K9me3 and are generally located near the nuclear periphery or nucleolus. This is different from TEAD1 patterns both in normal cells and within other regions of the same nuclei, where TEAD1 is distributed into many sub-resolution foci and associates with markers of active chromatin. We have used a combination of high-resolution microscopy, RNA-seq, ChIP-seq, and biochemical methods to identify the unique chromatin architecture of these cancer-associated large TEAD1 foci and propose that they represent a novel subtype of biomolecular condensate where normally activating transcription factors are recruited into repressive heterochromatin. As YAP1-TEAD complexes are important mediators of chromatin architecture and genome organization, these findings provide insight into how those mechanisms can be hijacked in cancer.