DNA methylation abnormalities in congenital heart disease.
DNA methylation abnormalities in congenital heart disease.
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DOI：
10.1080/15592294.2014.998536
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Pérez-Jurado LA
中科院分区：
文献类型：
--
作者：
Serra-Juhé C;Cuscó I;Homs A;Flores R;Torán N;Pérez-Jurado LA
先天性心脏缺陷是出生时最常见的畸形，也发生在约50%的唐氏综合征患者中。先天性心脏缺陷被认为有多因素病因，但主要原因在很大程度上是未知的。我们已经探索了胎儿心脏DNA与对照受试者血液DNA的总体甲基化谱：检测到与组织类型的绝对相关性。通路分析显示，在发育中的心脏DNA中，与肌肉收缩和心肌病相关的基因的差异甲基化显著富集。我们还研究了综合征型和非综合征型先天性心脏病的发育中心脏组织DNA的异常甲基化谱。平均而言，每个样品检测到3个异常甲基化区域，并且发现组间有18个区域差异甲基化。在参与生长调节、凋亡和叶酸途径的候选基因中检测到几个表位突变。一个可能的致病性高甲基化的几个基因内位点的MSX1基因，参与流出道形态发生，被发现在胎儿孤立的心脏畸形。此外，GATA4基因的高甲基化存在于有或没有先天性心脏缺陷的唐氏综合征胎儿中，以及孤立的心脏畸形胎儿中。检测到异常甲基化基因的表达失调。我们的数据表明，相关基因的表观遗传学改变存在于单独和综合征性心脏畸形胎儿的发育心脏DNA中。这些表型突变可能通过对基因表达的顺式作用而导致畸形的发病。
Congenital heart defects represent the most common malformation at birth, occurring also in ∼50% of individuals with Down syndrome. Congenital heart defects are thought to have multifactorial etiology, but the main causes are largely unknown. We have explored the global methylation profile of fetal heart DNA in comparison to blood DNA from control subjects: an absolute correlation with the type of tissue was detected. Pathway analysis revealed a significant enrichment of differential methylation at genes related to muscle contraction and cardiomyopathies in the developing heart DNA. We have also searched for abnormal methylation profiles on developing heart-tissue DNA of syndromic and non-syndromic congenital heart defects. On average, 3 regions with aberrant methylation were detected per sample and 18 regions were found differentially methylated between groups. Several epimutations were detected in candidate genes involved in growth regulation, apoptosis and folate pathway. A likely pathogenic hypermethylation of several intragenic sites at the MSX1 gene, involved in outflow tract morphogenesis, was found in a fetus with isolated heart malformation. In addition, hypermethylation of the GATA4 gene was present in fetuses with Down syndrome with or without congenital heart defects, as well as in fetuses with isolated heart malformations. Expression deregulation of the abnormally methylated genes was detected. Our data indicate that epigenetic alterations of relevant genes are present in developing heart DNA in fetuses with both isolated and syndromic heart malformations. These epimutations likely contribute to the pathogenesis of the malformation by cis-acting effects on gene expression.