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Epigenetic repression of retinoic acid responsive genes for cardiac outflow tract formation

Song, Yuntao
http://orcid.org/0000-0003-0218-8601
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563295948947138

Abstract Details

2019, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
Congenital heart diseases (CHDs) are the most common birth defects. About one-third of CHDs are caused by malformations of the outflow tract (OFT). The OFT is a portion of the ventricle derived from later differentiating cardiac progenitors called the second heart field (SHF) during heart development. Although the number of chambers among animal species may differ, regulation of SHF development is highly conserved in vertebrates. In the past few years, individual signaling pathways and transcription factors involved in SHF development have been well studied. However, coordinated transcriptional and epigenetic mechanisms that direct the development of SHF progenitors remain largely unknown. In this dissertation, we explored the requirement of the epigenetic regulator Histone deacetylase 1 (Hdac1) during the SHF development using the zebrafish mutant called cardiac really gone (crg). Although hdac1 is broadly expressed in the embryo during early development, we found that the loss of hdac1 in crg mutant zebrafish causes a specific deficit of ventricular cardiomyocytes (VCs) and smooth muscle in the OFT, which is due to decreased proliferation of cardiac progenitors in the SHF. Furthermore, we found that there is overlap between Hdac1 and retinoic acid (RA)-responsive genes, as increases in RA signaling produce similar OFT defects. Specifically, we identified that the ectopic expression of the RA-responsive gene ripply3, which acts as a transcriptional co-repressor for Tbx1, is partially responsible for the specific reduction of VCs in hdac1 mutants. Our study highlights that transcriptional repression via the epigenetic regulator Hdac1 facilitates OFT development through directly preventing the expression of the RA-responsive gene ripply3 within SHF progenitors. Our study of Hdac1 exemplifies the spatiotemporal role of a commonly expressed epigenetic regulator for heart development and how it may coordinate RA signaling. Overall, the information gained from this study may lead to new preventative therapies for a broad range of CHDs, including those found in Down Syndrome and RA embryopathy.
Joshua Waxman, Ph.D. (Committee Chair)
Brian Gebelein, Ph.D. (Committee Member)
Jerry Lingrel, Ph.D. (Committee Member)
S. Steven Potter, Ph.D. (Committee Member)
Katherine Yutzey, Ph.D. (Committee Member)
Aaron Zorn, Ph.D. (Committee Member)
130 p.
Developmental Biology
Heart development; Second heart field; Epigenetics; Retinoic acid; Ripply3

Recommended Citations

Citations

  • Song, Y. (2019). Epigenetic repression of retinoic acid responsive genes for cardiac outflow tract formation [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563295948947138

    APA Style (7th edition)

  • Song, Yuntao. Epigenetic repression of retinoic acid responsive genes for cardiac outflow tract formation. 2019. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563295948947138.

    MLA Style (8th edition)

  • Song, Yuntao. "Epigenetic repression of retinoic acid responsive genes for cardiac outflow tract formation." Doctoral dissertation, University of Cincinnati, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563295948947138

    Chicago Manual of Style (17th edition)

ucin1563295948947138
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This open access ETD is published by University of Cincinnati and OhioLINK.