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Note: thesis: Thesis (Ph. D.)--Brown University, 2019
Genre (aat): theses
Abstract: Biological systems must regulate complex gene transcriptional programs to mediate phenotypic response to diverse stimuli. Control of gene expression requires specific DNA sequence patterns called cis-regulatory elements (CREs). CREs may recruit single transcription factors (TFs) or specific TF combinations. The interplay between CREs and TFs in complex eukaryotic systems is not well understood. Drosophila dosage compensation is an excellent model to explore how CREs modulate transcription because all the genes along the length of a single chromosome are precisely co-regulated. In Drosophila, the Male-specific lethal complex (MSLc) localizes specifically to the single male X chromosome and increases transcription to equalize with that from the two female X chromosomes. MSLc targets X-linked regions known as “chromatin entry” sites (CES) that contain GA-rich CREs known as MSLc recruitment elements (MREs). GA-rich CREs are two-fold X-enriched, however, they are not sufficient to target MSLc. Additionally, CES cluster three-dimensionally but the mechanism by which this occurs remained unknown. MSLc requires an essential, non sex-specific, TF called Chromatin-linked Adapter for MSL proteins (CLAMP) in order to identify MREs. Unlike MSLc, CLAMP is not restricted to the X chromosome and binds GA-rich CREs genome-wide. Moreover, the mechanism by which a TF that binds to CREs genome-wide functions specifically on the X chromosome remained unknown. This dissertation provides insight into how CREs and TFs dynamics enable precise, context-specific, transcriptional regulation. First, I defined how subtle variations in CRE sequence composition, proximity, and genomic context influence TF recruitment using in vivo approaches (Chapter 2). Close MRE proximity is optimal for MSLc recruitment and flanking sequences can help optimal MREs overcome sub-optimal proximity. Second, I used machine-learning to develop a candidate list of other factors that may help MSLc to specifically identify GA-rich CREs on the X chromosome (Chapter 3). Lastly, I used chromosome conformation capture approaches to identify how three-dimensional clustering of CES is established; the locally-enriched transcription factor CLAMP promotes long-range interactions between CES on the X chromosome to recruit MSLc (Chapter 4). Overall, I provide key insight into how the genomic context of CREs regulates gene transcription within a complex biological system.
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Subject (fast) (authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/00898415")
Subject (fast) (authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/00940228")
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Subject (fast) (authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/00898408")
Subject (fast) (authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/00871990")
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Identifier: DOI: 10.26300/gpsn-6468
Access Condition: rights statement (href="http://rightsstatements.org/vocab/InC/1.0/"): In Copyright
Access Condition: restriction on access: Collection is open for research.
Type of Resource (primo): dissertations