Inhibition of Histone H3K9 Acetylation by Anacardic Acid Can Correct the Over-Expression of Gata4 in the Hearts of Fetal Mice Exposed to Alcohol during Pregnancy

PLoS One

Hui-Chao Sun¹  Wei-An Zhao¹  Ling-Juan Liu²  Jie Tian³  Chang Peng³  Min Zheng³  Xu-Pei Huang⁴  Jing Zhu⁵ 

[1] Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China;Department of Biomedical Science, Charlie E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida, United States of America;Heart Centre, Children's Hospital of Chongqing Medical University, Chongqing, China;Key Laboratory of Pediatrics in Chongqing, Chongqing, China;Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China

关键词: Alcohols;    Histones;    Heart;    Acetylation;    Pregnancy;    Gene expression;    Ethanol;    Gene regulation;   

DOI  :  10.1371/journal.pone.0104135

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Background Cardiovascular 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 Results Pregnant 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.Conclusions Our 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.

【 授权许可】

CC BY