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

Doctor's Name: 
Yuntao Song
Cincinnati Children's Hospital Medical Center

Collaboratively awarded through the CHF and AHA Congenital Heart Defect Research Awards

(Total Grant Amount $53,688; CHF portion = $16,583.15)

Congenital heart diseases (CHDs) are the most prevalent birth defects in newborns. One third of CHDs are attributed to defects in the cardiac outflow tract (OFT). Hence, a detailed understanding of how the OFT is formed in the embryo is important for the generation of novel strategies for the prevention and cure of these defects. In this study, we will investigate how a critical epigenetic regulator called histone deacetylase 1 (HDAC1) specifically promotes OFT development through interactions with a receptor for retinoic acid (RA), the most active metabolite of vitamin A and common teratogen, in gene regulation.

We identified a previous unappreciated requirement of HDAC1 in normal OFT development. Furthermore, we have identified that ripply3 as a candidate effector of OFT defects in HDAC1 mutants. Ripply3 is identified highly associated with Down Syndrome and is an RA responsive gene. Children with Down Syndrome and excess embryos RA both display higher probabilities of cardiac OFT defects. Thus, we are asking how HDAC1 represses of ripply3 expression and how the excess Ripply3 disrupts OFT formation. We will use a combination of molecular, cellular, and genetic tools to answer these questions.     

Epigenetic regulation is one the most important aspects that guides animal development. However, the epigenetic mechanisms regulating vertebrate OFT development are not understood. Our proposal will reveal unknown roles of a conserved epigenetic regulator, HDAC1, in the formation of the vertebrate cardiac OFT. Therefore, we will learn how the repressive activity of HDAC1 promotes normal heart development. Overall, our findings are likely to be broadly applicable to a number of developmental syndromes with a high frequency of CHDs, including Down Syndrome and RA embryopathy. Additionally, since HDAC inhibitors are commonly used as mood stabilizers and anti-epileptic therapies, the study will disclose potential side effects of these drugs on fetal OFT formation in pregnant women.

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