Application of transcriptomics, computational modeling, and evolutionary analysis to investigate the regulation of transcription elongation factors

Francette, Alex (2024) Application of transcriptomics, computational modeling, and evolutionary analysis to investigate the regulation of transcription elongation factors. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Between transcription initiation and termination, RNA Polymerase II (RNAPII) associates with a variety of transcription elongation factors. These proteins modulate RNAPII elongation rate, RNAPII processivity, and the activity of enzymes that co-transcriptionally process RNA. The evolutionarily conserved Paf1 complex (Paf1C), consisting of Paf1, Ctr9, Rtf1, Cdc73, and Leo1, associates with elongating RNAPII and has been implicated in a variety of co-transcriptional processes. Defects in Paf1C have been associated with disease states and misregulation of co-transcriptional events. Therefore, an understanding of how Paf1C functions in transcription elongation is paramount to understanding how these functions impact human health. Thus, for my dissertation, I investigated Paf1C and other transcription elongation factors to advance understanding of the fundamental processes underlying gene expression. Herein I describe my progress in characterizing the roles of Paf1C and other transcription elongation factors through multiple approaches. Through one investigation, I elucidate the direct and indirect contributions of Paf1C subunits to chromatin and transcription regulation using multi-omic and computational approaches. This work uncovers subunit-specific functions of Paf1C regulating transcription elongation processivity and an indirect role of Paf1C in modulating transcript processing through splicing. I have additionally developed a model of transcription elongation dynamics (TED) to predict how RNAPII elongation is altered in the short- and long-term absence of Paf1C. Furthermore, I interrogate the contributions of Paf1C-dependent histone modifications towards Paf1C-dependent transcriptional phenotypes. This work comprehensively analyzes both the immediate and extended roles of each Paf1C subunit in transcription elongation and transcript regulation. I also describe my contributions to another study characterizing the phylogenetics of core transcription elongation factors including Paf1C across the tree of life. In collaboration with Aakash Grover, we uncovered patterns of apparent reductive evolution which may render some transcription elongation factors disposable in select clades. This work reveals flexibility in the composition of the transcription elongation machinery across species. Together, this work advances our understanding of the fundamental biological processes regulating transcription in a model eukaryote and across all domains of life.

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Details

Item Type:	University of Pittsburgh ETD
Status:	Unpublished
Creators/Authors:	Creators Email Pitt Username ORCID Francette, Alex amfrancette@gmail.com amf198 0000-0003-1145-5847
ETD Committee:	Title Member Email Address Pitt Username ORCID Committee Chair Arndt, Karen arndt@pitt.edu arndt 0000-0003-1320-9957 Committee Member Kaplan, Craig craig.kaplan@pitt.edu craig.kaplan 0000-0002-7518-695X Committee Member Hainer, Sarah sarah.hainer@pitt.edu sarah.hainer 0000-0003-0503-1183 Committee Member Rebeiz, Mark rebeiz@pitt.edu rebeiz 0000-0001-5731-5570 Committee Member McManus, Charles mcmanus@andrew.cmu.edu 0000-0002-6605-2642
Date:	18 December 2024
Date Type:	Publication
Defense Date:	10 September 2024
Approval Date:	18 December 2024
Submission Date:	25 September 2024
Access Restriction:	No restriction; Release the ETD for access worldwide immediately.
Number of Pages:	301
Institution:	University of Pittsburgh
Schools and Programs:	Dietrich School of Arts and Sciences > Biological Sciences
Degree:	PhD - Doctor of Philosophy
Thesis Type:	Doctoral Dissertation
Refereed:	Yes
Uncontrolled Keywords:	Genetics, Molecular Biology, Transcription, Gene Expression, Paf1C
Date Deposited:	18 Dec 2024 20:43
Last Modified:	18 Dec 2024 20:43
URI:	http://d-scholarship.pitt.edu/id/eprint/46991

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