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A Potential Role for Phase Separation in NUT Carcinoma

NUT carcinoma (NC) is a highly aggressive and poorly differentiated type of cancer, mostly occurring in human midline organs. The disease is characterized by chromosomal translocations that involve NUT on chromosome 15 and a partner gene. In about 75% of cases that partner gene has been reported to be BRD4 on chromosome 19. The mechanism by which the BRD4-NUT fusion product causes cancer remains poorly understood. It has been reported that BRD4 protein by itself can form liquid-like intranuclear condensates, which have been shown to be associated with super-enhancers, to control gene expression. Previous studies have also shown that the BRD4-NUT fusion protein forms large, round condensates in cells. I hypothesize that these condensates represent aberrant phase separation of BRD4, which alters transcription, leading to cell transformation.

In my studies, I observed that upon expression in cells, BRD4-NUT fusion protein forms large condensates, that are highly dynamic, suggesting that they might exhibit liquid-like properties. I also determined that there is only a small part of NUT that is required to be in fusion with BRD4 for the formation of these nuclear condensates and that same part is responsible for the interaction with a histone acetyltransferase, p300. Therefore, I subsequently tested the expression of an engineered BRD4-p300 fusion in cells and learned that this fusion is also sufficient to form condensates, which exhibit similar properties to the ones formed by BRD4-NUT. I then expressed different mutants of BRD4-p300 fusion in cells and found that different fragments of p300 collectively contribute to condensates formation.

I am currently in the process of testing how the expression of the different fusion constructs influences gene expression. By combining the RNAseq and ChIP-seq experiments with microscopy, I aim to find out if there is a link between the aberrant phase separation of BRD4-NUT and cell transformation from healthy to diseased cells in Nut Carcinoma.


Pak C.W., Kosno M., Holehouse A.S., Padrick S.B., Mittal A., Ali R., Yunus A.A., Liu D.R., Pappu R.V., Rosen M.K. “Sequence Determinants of Intracellular Phase Separation by Complex Coacervation of a Disordered Protein.” Molecular Cell. 2016. Jul 7;63(1):72-85.


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