Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease
Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease
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DOI：
10.1172/jci.insight.95085
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发表时间：
2017-10-19
期刊：
影响因子：
8
通讯作者：
Garg, Vidu
中科院分区：
文献类型：
--
作者：
Basu, Madhumita;Zhu, Jun-Yi;Garg, Vidu
出生缺陷是婴儿死亡的主要原因，是由遗传和环境因素综合作用引起的。环境风险因素可能通过改变胚胎发育过程中的关键分子途径而导致遗传易感婴儿的出生缺陷，但基因-环境相互作用的实验证据有限。与母体糖尿病相关的胎儿高血糖导致先天性心脏病（CHD）风险增加5倍，但这种相关性的分子基础尚不清楚。在这里，我们发现母体高血糖对心脏发育的影响是由Notch 1单倍不足引起的，Notch 1是一种已知引起CHD的关键转录调节因子。使用ATAC-seq，我们发现高血糖降低了内皮NO合酶（Nos 3）位点的染色质可及性，导致NO合成减少。转录的Jarid 2，调节组蛋白甲基转移酶复合物，增加响应减少NO，这种上调直接导致抑制Notch 1的表达水平低于正常心脏发育所需的阈值。我们使用果蝇母体糖尿病模型扩展了这些发现，该模型揭示了这种相互作用的进化保守性和Jarid 2介导的机制。这些发现确定了母体高血糖和Notch信号之间的基因-环境相互作用，并支持环境因素导致遗传易感婴儿出生缺陷的模型。
Birth defects are the leading cause of infant mortality, and they are caused by a combination of genetic and environmental factors. Environmental risk factors may contribute to birth defects in genetically susceptible infants by altering critical molecular pathways during embryogenesis, but experimental evidence for gene-environment interactions is limited. Fetal hyperglycemia associated with maternal diabetes results in a 5-fold increased risk of congenital heart disease (CHD), but the molecular basis for this correlation is unknown. Here, we show that the effects of maternal hyperglycemia on cardiac development are sensitized by haploinsufficiency of Notch1, a key transcriptional regulator known to cause CHD. Using ATAC-seq, we found that hyperglycemia decreased chromatin accessibility at the endothelial NO synthase (Nos3) locus, resulting in reduced NO synthesis. Transcription of Jarid2, a regulator of histone methyltransferase complexes, was increased in response to reduced NO, and this upregulation directly resulted in inhibition of Notch1 expression to levels below a threshold necessary for normal heart development. We extended these findings using a Drosophila maternal diabetic model that revealed the evolutionary conservation of this interaction and the Jarid2-mediated mechanism. These findings identify a gene-environment interaction between maternal hyperglycemia and Notch signaling and support a model in which environmental factors cause birth defects in genetically susceptible infants.