ORCID
https://orcid.org/0000-0002-3137-6583
Date of Award
9-5-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Cardiogenesis and the maintenance of cardiac physiology necessitate dynamic and carefully coordinated transcription programs. Studies in a many systems – both in vitro and in vivo – have elucidated critical signaling pathways, including Bmp, Fgf, Wnt, and Notch that induce a cardiogenic transcription program, thereby driving cardiac specification and differentiation. Recently, studies have discovered additional regulation at the epigenetic level that contributes to the tight temporal and spatial control of cardiac gene expression during development. Because transcriptional regulation is essential to cardiogenesis, changes in transcriptional regulation result in developmental defects, including but not limited to CHDs, the leading inborn cause of mortality in infants. Intellectual disability (ID) is a general neurodevelopmental disorder that affects 2-3% of the general population. Seventy-five to 90 percent of affected individuals have mild ID, with ~25% of cases being caused by a genetic disorder. Among children, the cause of ID is unknown for ~33-50% of cases, with ~5% of cases due to inheritance. While primarily characterized by significant sub-average cognitive function and deficits in adaptive behavior, ID often presents with other aberrant phenotypes, including but not limited to craniofacial deformities and congenital heart disease. These syndromic forms of intellectual disability frequently have a genetic basis. For example, pathogenic variants in key components of TATA-binding protein associated factors (TAFs) have recently been identified in a subset of patients with intellectual disability, craniofacial hypoplasia, and congenital heart disease. This syndrome has been termed as a TAFopathy and includes mutations in TATA binding protein (TBP), TAF1, TAF2, and TAF6. The underlying mechanism by which TAFopathies give rise to neurodevelopmental, craniofacial, and cardiac abnormalities remains to be defined. To identify and understand key roles of TAFs in TAFopathies, we used zebrafish (Danio rerio) as a model organism. Although the zebrafish has a simpler structure than the mammalian counterpart, it possesses analogs of major body components and utilizes similar cellular and molecular strategies to assemble them, including but not limited to the nervous system and the heart. The transparency of the embryos, combined with their low cost, fecundity, rapid development and external fertilization, allows us to perform direct, non-invasive observation of developmental events. Through a forward genetic screen in zebrafish, we have recovered a lethal nonsense mutation in TAF5. Mutant embryos exhibited craniofacial hypoplasia, ventricular hypoplasia, and heart failure at 96 hours post-fertilization. CRISPR/CAS9 mediated gene editing revealed that this phenotype was recapitulated in taf1-/- and taf5-/- zebrafish. Mechanistically, taf5-/- zebrafish displayed perturbations in metabolic gene expression and metabolism as evidenced by RNA sequencing, RT-PCR, respiration assays, and metabolite studies. Collectively, these findings suggest that the TAF complex contributes to neurologic, craniofacial, and cardiac development through regulation of metabolism.
Language
English (en)
Chair and Committee
Kory Lavine
Recommended Citation
Leid, Jamison Maxwell, "TAFopathies Result from Derangements in Transcriptional Regulation of Metabolism" (2023). Arts & Sciences Electronic Theses and Dissertations. 3147.
https://openscholarship.wustl.edu/art_sci_etds/3147