Center for Cardiovascular Research and Heart Center, Nationwide Children's Hospital, Columbus, Ohio, USA.
Center for Genetic Medicine Research, Children's National Health System, Washington, DC, USA.
JCI Insight. 2017 Oct 19;2(20):95085. doi: 10.1172/jci.insight.95085.
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.
出生缺陷是婴儿死亡的主要原因,它们是由遗传和环境因素共同引起的。环境风险因素可能通过在胚胎发生过程中改变关键的分子途径,导致遗传上易感的婴儿出现出生缺陷,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会使先天性心脏病 (CHD) 的风险增加 5 倍,但这种相关性的分子基础尚不清楚。在这里,我们表明 Notch1 的杂合功能不足会使母体高血糖对心脏发育的影响变得敏感,Notch1 是一种已知会导致 CHD 的关键转录调节剂。通过 ATAC-seq,我们发现高血糖会降低内皮型一氧化氮合酶 (Nos3) 基因座的染色质可及性,从而导致 NO 合成减少。Jarid2 的转录,一种组蛋白甲基转移酶复合物的调节剂,对减少的 NO 有反应性,这种上调直接导致 Notch1 表达水平抑制到低于正常心脏发育所需的阈值。我们使用一种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和 Jarid2 介导的机制在进化上的保守性。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,并支持了这样一种模型,即环境因素会导致遗传上易感的婴儿出现出生缺陷。