YY1 Mediated Competitve Regulation: A Governing Principle Behind Phenotype-Specific Gene Expression in Vascular Smooth Muscle Cells

dc.contributor.advisorStephen R. Grant
dc.contributor.committeeMemberNeeraj Agarwal
dc.contributor.committeeMemberPeter B. Raven
dc.creatorRoberts, Leslie Don
dc.description.abstractLeslie Don Roberts, YYI Mediated Competitive Regulation: A governing principle behind phenotype-specific gene expression in vascular smooth muscle cells. Doctor of Philosophy (Biomedical Science), July 2005. The vascular smooth muscle cell (VSMC) lacks the typical phenotypic restriction that limit most cell-types to expressing a single phenotype, as a result, these cells are uniquely suited to wound repair, as well as, exacerbating several vascular disease-states. While much is known regarding the specific transcription factors that drive phenotype-specific gene expression the mechanisms that regulate the transition between phenotype-specific gene programs remain poorly defined. To further explore these mechanisms, we sought to better understand how VSMCs stably express their default contractile-specific gene program despite the inherent instabilities of their environment. This study explored the regulatory implications of a yet undescribed regulatory domain, that resides with a high-frequency in the promoters of the most contractile-specific gene. These domains, which we term dual regulatory domains (DRD), orient the core binding site for the transcriptional repressor Ying Yang-1 in close proximity to, or overlapping with, the core binding site for a variety of transcriptional activators. This study specifically examines the regulatory implications at two DRD where YY1 competes with the transcriptional activators C/EBPβ (C/CAAT-enhancer binding protein beta). Our findings demonstrate: i.) YY1 acts as a dominant, negative, regulator of the smooth muscle myosin heavy chain (SM-MHC) gene promoter; ii.) YY1 binds to, and repressing from, multiple sites within the regulatory context of this promoter; and iii.) The transactivation potential of C/EBPβ completes with transrepressive potential of YY1 for regulatory control over SM-MHC promoter activity and does so in a stoichiometric-dependent fashion. These findings argue that the relative concentrations of YY1 define the effective dose required of specific transcriptional activators to complete with and override the repressive effect of YY1, and by doing so, directly dictate which genes will be expressed.
dc.subjectCell and Developmental Biology
dc.subjectCell Biology
dc.subjectCellular and Molecular Physiology
dc.subjectDevelopmental Biology
dc.subjectGenetic Phenomena
dc.subjectGenetic Processes
dc.subjectGenetics and Genomics
dc.subjectGenetic Structures
dc.subjectLife Sciences
dc.subjectMedical Cell Biology
dc.subjectMedical Genetics
dc.subjectMedicine and Health Sciences
dc.subjectOther Cell and Developmental Biology
dc.subjectOther Genetics and Genomics
dc.subjectVascular smooth muscle cell
dc.subjectphenotypic restriction
dc.subjectvascular disease states
dc.subjectdual regulatory domains
dc.subjectYing Yang-1
dc.subjecttranscriptional activators
dc.subjectsmooth muscle myosin heavy chain gene promoter
dc.subjectgene expression
dc.titleYY1 Mediated Competitve Regulation: A Governing Principle Behind Phenotype-Specific Gene Expression in Vascular Smooth Muscle Cells
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplineBiomedical Sciences
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy


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