PROJECT SUMMARY/ABSTRACT
Condensate models of transcription in which dynamic, membraneless bodies in the nucleus concentrate large
numbers of transcriptional components have recently been described, providing a new framework to solve
mysteries in transcription. Early studies of RNA in complex coacervates revealed that RNA can have positive
and negative effects on proteinaceous condensates and may operate to control gene expression. Preliminary
data confirms the prediction that RNAs at low levels, like those present during early transcription initiation, will
stimulate condensates with the coactivator Mediator, and at higher levels, dissolve them. Transcriptional
dysregulation is a hallmark of cancer, but how oncogenic transcription maintains high levels of expression
remains unresolved. It is possible that the RNA-mediated behavior of condensates is altered in cancerous
cells, and perhaps key oncogenes like MYC have a function in this behavior that has not been described
before. Thus, this proposal will test the hypothesis that excess levels of oncogenic proteins compensate for
higher RNA production by making transcriptional condensates more resistant to dissolution. The drivers of
oncogenesis and metastasis may have a physicochemical effect on transcriptional dysregulation that was not
anticipated before the advent of the condensate model of transcription. To test this hypothesis, the proposal
includes aims that will characterize oncogenic condensates and evaluate the ability of oncogenic proteins to
stabilize them in cancer cells. As part of this proposal, relevant training will include strengthening and learning
new skills in super-resolution microscopy, cellular engineering, protein biochemistry, and cancer biology. The
results from this proposal will provide direct evidence that biophysical phenomenon, mediated by the product of
transcription, regulate gene expression in normal and malignant states. They will provide potential new routes
to develop therapies against hard-to-target transcription factors and transcriptional dependencies in cancer.