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Unraveling Mechanisms of Transcriptional Repression: Novel Insights from Brinker

Upadhyai, Priyanka (2013) Unraveling Mechanisms of Transcriptional Repression: Novel Insights from Brinker. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Transcriptional repressors bind cis-regulatory elements of target genes in a sequence specific manner. To antagonize transcription, repressors primarily function by recruiting accessory proteins, co-repressors, which in turn largely function by modifying chromatin structure. Although a repressor could function by recruiting just a single co-repressor, many recruit more than one, with Brinker (Brk) from Drosophila recruiting the co-repressors, CtBP and Groucho (Gro), in addition to possessing a third repression domain, 3R. Previous studies indicated that Gro is sufficient for Brk to repress target genes in the wing imaginal disc, questioning why it should need to recruit CtBP, a ’short-range’ co-repressor compared to Gro that can function over longer distances. To resolve this I have used genomic engineering to generate a series of endogenous brk mutants that are unable to recruit Gro, CtBP and/or have the 3R domain deleted. Analysis of these mutants reveals that while the recruitment of Gro is necessary and is almost sufficient for Brk to make a morphologically wild-type fly, it is insufficient during oogenesis where Brk must utilize CtBP and 3R to pattern the egg-shell appropriately. Gro insufficiency during oogenesis can be explained by its downregulation in Brk-expressing cells through phosphorylation downstream of EGFR signaling, thus making it unavailable for Brk which must then resort to CtBP and/or 3R for repressive activity. The present study dissects the mechanism of activity of a transcription factor and its co-repressors and is the first to do so in multicellular eukaryotes in a physiologically relevant manner; additionally its findings provide a better understanding of why transcription factors in general may utilize more than one co-repressor.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Upadhyai, Priyankapru2@pitt.eduPRU2
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairCampbell, Gerardcamp@pitt.eduCAMP
Committee MemberKaren , Arndtarndt@pitt.eduARNDT
Committee MemberStronach, Bethstronach@pitt.eduSTRONACH
Committee MemberVandemark, Andrewandyv@pitt.eduANDYV
Committee MemberSchmidt, Martinmcs2@pitt.eduMCS2
Date: 30 September 2013
Date Type: Publication
Defense Date: 29 May 2013
Approval Date: 30 September 2013
Submission Date: 16 July 2013
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 173
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: repression, co-repressor, Brinker, Groucho
Date Deposited: 30 Sep 2013 21:08
Last Modified: 15 Nov 2016 14:14


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