DeMoya, Ricardo
(2023)
SIN3A associated proteins (SAPs) and zebrafish cardiogenesis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Congenital heart diseases account for approximately 1% of all live births world-wide. The exact causes of CHDs are largely unknown with recent evidence pointing to complex genetics and environmental influences. Critical CHDs are classified as those causing infantile cyanosis, and in most cases are lethal without surgical intervention. Hypoplastic left heart syndrome (HLHS) is a critical congenital heart disease where the left structures of the heart are reduced in size. A forward genetic screen in mice identified SIN3A associated protein 130kDa (SAP130), a protein that interacts with the chromatin modifying SIN3A/HDAC1 complex, as a gene contributing to the genetic etiology of HLHS. In this dissertation, I characterized the role of zebrafish sap130 genes in heart development. Loss of sap130a, one of two Sap130 orthologs, resulted in smaller ventricle size, a phenotype reminiscent to the hypoplastic left ventricle in mice. While cardiac progenitors were normal during somitogenesis, diminution of the ventricle size suggest the second heart field was the source of the defect. To explore the role of sap130a in gene regulation, transcriptome profiling was performed after the heart tube formation. Genes involved in cardiac contraction and conduction were dysregulated in sap130a, but not in sap130b mutants. Confocal light sheet analysis measured deficits in cardiac output in sap130a mutants supporting the notion that cardiomyocyte sarcomere maturation was disrupted. Lineage tracing experiments revealed a significant reduction of Second Heart Field (SHF) cells in the ventricle that resulted in increased outflow tract size. These data suggest that sap130a is involved in cardiogenesis via regulating the accretion of SHF cells to the growing ventricle and in their subsequent maturation for cardiac function. Further, genetic studies revealed an interaction between hdac1 and sap130a, in the incidence of small ventricles. To further explore other proteins in the Sin3a/Hdac complex, I generated mutants in sin3ab and sap18 genes. Both MZsin3ab and MZsap18 mutants developed smaller ventricle phenotype by 48hpf, that further highlights the importance of this complex in early heart morphogenesis. This suggests that the SIN3A complex is critical for the proper formation and function of the heart in the developing embryo.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
8 December 2023 |
| Date Type: |
Publication |
| Defense Date: |
1 June 2023 |
| Approval Date: |
8 December 2023 |
| Submission Date: |
20 July 2023 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
142 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Developmental Biology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
cardiac development, second heart field, SIN3A/HDAC complex, sap130a,zebrafish |
| Date Deposited: |
08 Dec 2023 14:00 |
| Last Modified: |
08 Dec 2023 14:00 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45123 |
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