Abstract
BackgroundCardiovascular malformations can be caused by abnormalities in Gata4 expression during fetal development. In a previous study, we demonstrated that ethanol exposure could lead to histone hyperacetylation and Gata4 over-expression in fetal mouse hearts. However, the potential mechanisms of histone hyperacetylation and Gata4 over-expression induced by ethanol remain unclear.Methods and ResultsPregnant mice were gavaged with ethanol or saline. Fetal mouse hearts were collected for analysis. The results of ethanol fed groups showed that global HAT activity was unusually high in the hearts of fetal mice while global HDAC activity remained unchanged. Binding of P300, CBP, PCAF, SRC1, but not GCN5, were increased on the Gata4 promoter relative to the saline treated group. Increased acetylation of H3K9 and increased mRNA expression of Gata4, α-MHC, cTnT were observed in these hearts. Treatment with the pan-histone acetylase inhibitor, anacardic acid, reduced the binding of P300, PCAF to the Gata4 promoter and reversed H3K9 hyperacetylation in the presence of ethanol. Interestingly, anacardic acid attenuated over-expression of Gata4, α-MHC and cTnT in fetal mouse hearts exposed to ethanol.ConclusionsOur results suggest that P300 and PCAF may be critical regulatory factors that mediate Gata4 over-expression induced by ethanol exposure. Alternatively, P300, PCAF and Gata4 may coordinate over-expression of cardiac downstream genes in mouse hearts exposed to ethanol. Anacardic acid may thus protect against ethanol-induced Gata4, α-MHC, cTnT over-expression by inhibiting the binding of P300 and PCAF to the promoter region of these genes.
Highlights
In children, congenital heart disease (CHD) accounts for nearly one-third of all major congenital anomalies [1], a major cause of death in infants of 1 year of age or below [2]
Our results suggest that P300 and PCAF may be critical regulatory factors that mediate Gata4 over-expression induced by ethanol exposure
P300, PCAF and Gata4 may coordinate over-expression of cardiac downstream genes in mouse hearts exposed to ethanol
Summary
Congenital heart disease (CHD) accounts for nearly one-third of all major congenital anomalies [1], a major cause of death in infants of 1 year of age or below [2]. Many studies indicate that the Gata transcription factor plays a critical role during cardiogenesis, from primitive heart tube to maturation i.e. the four-chambered heart [8,9,10,11] Both genetics and epigenetics play a part in regulating the expression of Gata and alterations that lead to uncontrolled expression of Gata could affect normal development of the heart. We have demonstrated that high consumption of alcohol or its metabolites can induce histone hyperacetylation that leads to over-expression of Gata4 [12,13]. It is not clear whether alcohol exposure increases myocardial histone acetylation or Gata over-expression in developing hearts. The potential mechanisms of histone hyperacetylation and Gata overexpression induced by ethanol remain unclear
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