Peng Chang, Zhu Jing, Sun Hui-Chao, Huang Xu-Pei, Zhao Wei-An, Zheng Min, Liu Ling-Juan, Tian Jie
Heart Centre, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.
Key Laboratory of Pediatrics in Chongqing, Chongqing, China; Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.
PLoS One. 2014 Aug 7;9(8):e104135. doi: 10.1371/journal.pone.0104135. eCollection 2014.
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.
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.
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.
心血管畸形可能由胎儿发育过程中Gata4表达异常引起。在先前的一项研究中，我们证明乙醇暴露可导致胎鼠心脏中组蛋白高度乙酰化和Gata4过表达。然而，乙醇诱导组蛋白高度乙酰化和Gata4过表达的潜在机制仍不清楚。
给怀孕小鼠灌胃乙醇或生理盐水。收集胎鼠心脏进行分析。乙醇喂养组的结果显示，胎鼠心脏中的总体组蛋白乙酰转移酶（HAT）活性异常高，而总体组蛋白去乙酰化酶（HDAC）活性保持不变。与生理盐水处理组相比，Gata4启动子上P300、CBP、PCAF、SRC1（而非GCN5）的结合增加。在这些心脏中观察到H3K9乙酰化增加以及Gata4、α-肌球蛋白重链（α-MHC）、心肌肌钙蛋白T（cTnT）的mRNA表达增加。用泛组蛋白乙酰化酶抑制剂漆树酸处理可减少P300、PCAF与Gata4启动子的结合，并在有乙醇存在的情况下逆转H3K9高度乙酰化。有趣的是，漆树酸减弱了乙醇暴露的胎鼠心脏中Gata4、α-MHC和cTnT的过表达。
我们的结果表明，P300和PCAF可能是介导乙醇暴露诱导Gata4过表达的关键调节因子。或者，P300、PCAF和Gata4可能协同调节乙醇暴露的小鼠心脏中心脏下游基因过表达。因此，漆树酸可能通过抑制P300和PCAF与这些基因启动子区域的结合来预防乙醇诱导的Gata4、α-MHC、cTnT过表达。
