Please join us for the next NIPM Seminar Thursday, February 23, 2023, from 12:00 pm - 1:30 pm with Kyle Eagen, Ph.D. Assistant Professor, Baylor College of Medicine
Title: Nuclear Compartment Formation by an Oncogenic Fusion Protein
Abstract:
Chromosome compartments are important features of nuclear organization but have an unclear mechanism of formation and indeterminate functional significance. BRD4-NUT, the fusion oncoprotein causal for NUT carcinoma, forms broad hyperacetylated domains of chromatin. We find long-range chromatin interactions spanning tens to hundreds of megabases between hyperacetylated chromatin domains. Domain-domain contacts occur both within and between chromosomes forming a BRD4-NUT-driven nuclear compartment. Intra-compartment interactions are exceptionally strong for the BRD4-NUT-driven nuclear compartment; much more so than any of the other previously identified nuclear compartments. We also find that degradation of bromo- and extraterminal domain (BET) proteins by a small-molecule proteolysis targeting chimera (PROTAC) results in collapse of the BRD4-NUT-driven nuclear compartment. Genes within the BRD4-NUT-driven compartment are highly transcribed. However, transcription is not required to maintain chromatin contacts within the compartment and contacts between newly acetylated regions are formed after inhibiting RNA polymerase II initiation. In summary, we provide empirical evidence that "like attracts like" chromatin interactions result in nuclear compartment formation. We also show that an oncogenic fusion protein can drive compartment formation identifying an additional modality by which chromosome folding is compromised in cancer. Small molecules that target BET proteins cause NUT carcinoma cells to differentiate and abolish the BRD4-NUT-driven compartment, establishing the principle of pharmacological intervention of aberrant chromatin structure as a novel therapeutic approach for the treatment of human disease.
Zoom Meeting
https://us02web.zoom.us/j/84602088451?pwd=MG1ZM1JTallKeEVRSzI2YXByQk9aZz09
Meeting ID: 846 0208 8451
Passcode: 985558
In-person location: HRC 112