Forman-Rubinsky, Rachel Emma
(2024)
Creation of a single-cell atlas of the injured zebrafish heart uncovers the importance of cited4a in cardiomyocyte maturation during regeneration.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Myocardial infarction leaves the heart permanently damaged and more susceptible to future cardiac failure. This is because almost all mammalian adult cardiomyocytes are in a post mitotic, non-proliferative state and therefore fail to replace the damaged tissue. In contrast, zebrafish can fully regenerate their hearts following injury through the proliferation of existing cardiomyocytes and have become an important tool for identifying molecular mechanisms driving heart regeneration. Using snRNA sequencing and multiplexed RNAscope in situ hybridization, we have shown that zebrafish CMs are heterogeneous and there are subpopulations of cardiomyocytes with distinct transcriptional responses to injury. We also show similarities to cardiomyocyte populations identified in regenerating neonatal mouse hearts. cited4a, a transcriptional co-activator classified by its interaction with the CBP/p300 complex, is increased at the onset of cardiomyocyte proliferation and expressed highest in mature, non-proliferating cardiomyocytes following injury. We created two cited4a mutant zebrafish lines using CRISPR/Cas9. Both mutant alleles contain deletions that cause a frameshift and early stop codon. We show that cited4a is involved in maintaining cardiomyocyte maturation and loss of cited4a allows for more cardiomyocytes to dedifferentiate and proliferate following injury, leading to an acceleration of regeneration. This response to injury and the role of cited4a could be important for maintaining heart function during regeneration and limiting excessive cardiac growth. Transcriptional analysis of cited4a mutants suggests deficiencies in sarcomere and mitochondrial structure and function. Furthermore, many of the decreased transcripts are targets of Estrogen-Related Receptor (ERR)-mediated cardiomyocyte maturation programs. Like ERR⍺/
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
14 October 2024 |
| Date Type: |
Publication |
| Defense Date: |
18 April 2024 |
| Approval Date: |
14 October 2024 |
| Submission Date: |
3 May 2024 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
155 |
| 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: |
regeneration heart zebrafish |
| Date Deposited: |
14 Oct 2024 14:23 |
| Last Modified: |
14 Oct 2024 14:23 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46361 |
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