Mechanisms of transcription elongation control by the biomolecular condensate forming BET family protein BRD4

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Transcription elongation by RNA polymerase II (Pol II) has emerged as a regulatory hub in gene expression of metazoans. A major control point occurs during early transcription elongation before paused Pol II is released into productive transcription elongation to allow the synthesis of nascent RNAs. Prior research has linked the biomolecular condensate forming BET family protein BRD4, that has emerged as a therapeutic target in a range of human diseases, with transcription elongation. Our previous research has shown that acute loss of BRD4 leads to an immediate accumulation of Pol II in the promoter-proximal region of the vast majority of genes which is accompanied by a collapse of transcription elongation. Our previous research has also revealed that BRD4 is required for the recruitment of the PAF complex, an integral component of the productive Pol II elongation complex, during the early elongation control point. These data suggest that BRD4 plays a general and positive role in transcription elongation to enable nascent RNA synthesis. In this project, we aim to determine the specific and direct roles of BRD4 in the regulation of transcription elongation by Pol II in the native chromatin environment of human cells. The functional studies also aim to reveal the implication of BRD4 biomolecular condensates in transcription elongation in cells. To achieve the objectives, we will apply a high-resolution functional multiomics approach in combination with super-resolution microscopy.