Studies of the Molecular Features of Brd4-Nut and P300 That Contribute to Condensate Formation and Transcriptional Regulation

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dc.contributor.advisorKohler, Jennifer J.en
dc.contributor.committeeMemberTu, Benjaminen
dc.contributor.committeeMemberHenne, W. Mikeen
dc.contributor.committeeMemberBrekken, Rolf A.en
dc.contributor.committeeMemberLiszczak, Glenen
dc.contributor.committeeMemberRosen, Michael K.en
dc.creatorKosno, Martyna Olgaen
dc.creator.orcid0000-0002-1281-6061
dc.date.accessioned2023-06-07T18:16:38Z
dc.date.available2023-06-07T18:16:38Z
dc.date.created2023-05
dc.date.issued2023-05-01T05:00:00.000Z
dc.date.submittedMay 2023
dc.date.updated2023-06-07T18:16:39Z
dc.description.abstractAberrant formation of biomolecular condensates has been proposed to play a role in several cancers. The oncogenic fusion protein Brd4-Nut drives aberrant gene expression and forms condensates in Nut Carcinoma (NC). It has not been clear how these condensates form and whether they modulate gene expression. Here, I dissected the molecular features of Brd4-Nut and a histone acetyltransferase (HAT), p300, and analyzed their contribution to condensate formation and transcriptional changes. I determined that a minimal fragment of Nut (MIN) in fusion with Brd4 is necessary and sufficient for binding to p300, and for condensate formation. A Brd4-p300 fusion protein also forms condensates and drives a transcriptional profile similar to Brd4-Nut(MIN). The intrinsically disordered regions, transcription factor - binding domains, and HAT activity of p300 all collectively contribute to condensate formation. Conversely, only HAT activity appears to be necessary to mimic the transcriptional profile of cells expressing Brd4-Nut. My results suggest that interaction of Brd4-Nut with p300 is important for aberrant condensate formation, and that multiple, yet distinct, regions of p300 contribute to condensate formation and transcriptional regulation.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1381370396
dc.identifier.urihttps://hdl.handle.net/2152.5/10069
dc.language.isoenen
dc.subjectCarcinoma, Squamous Cellen
dc.subjectCell Cycle Proteinsen
dc.subjectE1A-Associated p300 Proteinen
dc.subjectGene Expression Regulation, Neoplasticen
dc.subjectTranscription Factorsen
dc.titleStudies of the Molecular Features of Brd4-Nut and P300 That Contribute to Condensate Formation and Transcriptional Regulationen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineBiological Chemistryen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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