Life-long epigenetic programming of cortical architecture by maternal 'Western' diet during pregnancy [RRBS]

The evolution of human diets led to preferences towards polyunsaturated fatty acid (PUFA) content with ‘Western’ diets enriched in ω-6 PUFAs. Mounting evidence points to ω-6 PUFA excess limiting metabolic and cognitive processes that define longevity in humans. When chosen during pregnancy, ω-6 PUFA-enriched ‘Western’ diets can reprogram maternal bodily metabolism with maternal nutrient supply precipitating the body-wide imprinting of molecular and cellular adaptations at the level of long-range intercellular signaling networks in the unborn fetus. Even though unfavorable neurological outcomes are amongst the most common complications of intrauterine ω6 PUFA excess, cellular underpinnings of life-long modifications to brain architecture remain unknown. Here, we show that nutritional ω-6 PUFA-derived endocannabinoids desensitize CB1 cannabinoid receptors, thus inducing epigenetic repression of transcriptional regulatory networks controlling neuronal differentiation. We found that cortical neurons lose their positional identity and axonal selectivity when mouse fetuses are exposed to excess ω-6 PUFAs in utero. Conversion of ω-6 PUFAs into endocannabinoids disrupted the temporal precision of signaling at neuronal CB1 cannabinoid receptors, chiefly deregulating Stat3-dependent transcriptional cascades otherwise required to execute neuronal differentiation programs. Global proteomics identified the immunoglobulin family of cell adhesion molecules (IgCAMs) as direct substrates, with DNA methylation and chromatin accessibility profiling uncovering epigenetic reprogramming at >1,400 sites in neurons after prolonged cannabinoid exposure. We found anxiety and depression-like behavioral traits to manifest in adult offspring, which is consistent with genetic models of reduced IgCAM expression, to suggest causality for cortical wiring defects. Overall, our data uncover a regulatory mechanism whose disruption by maternal food choices could limit an offspring’s brain function for life.

人类饮食的演化使得人们偏好多不饱和脂肪酸（polyunsaturated fatty acid, PUFA）的摄入，而“西式”饮食富含ω-6多不饱和脂肪酸。越来越多的证据表明，ω-6多不饱和脂肪酸过量会限制决定人类寿命的代谢与认知过程。若孕期选择富含ω-6多不饱和脂肪酸的“西式”饮食，会重塑母体代谢，母体的营养供给会促使未出生胎儿全身范围内，在长距离细胞间信号网络层面留下分子与细胞适应的印记。尽管不良神经结局是宫内ω-6多不饱和脂肪酸过量最常见的并发症之一，但大脑结构终身改变的细胞基础仍未明确。本研究发现，源自膳食ω-6多不饱和脂肪酸的内源性大麻素（endocannabinoids）会使CB1大麻素受体（CB1 cannabinoid receptors）脱敏，从而诱导控制神经元分化的转录调控网络发生表观遗传抑制（epigenetic repression）。我们发现，当小鼠胎儿在宫内暴露于过量ω-6多不饱和脂肪酸时，皮层神经元会丧失其位置身份与轴突选择性。ω-6多不饱和脂肪酸转化为内源性大麻素后，会破坏神经元CB1大麻素受体信号传导的时间精度，主要是异常调控原本执行神经元分化程序所需的Stat3依赖型转录级联反应。全局蛋白质组学（global proteomics）分析将细胞黏附分子免疫球蛋白家族（immunoglobulin family of cell adhesion molecules, IgCAMs）鉴定为直接底物；DNA甲基化（DNA methylation）与染色质可及性（chromatin accessibility）分析显示，在长期暴露于大麻素后，神经元中超过1400个位点发生了表观遗传重编程（epigenetic reprogramming）。我们还发现成年后代会表现出焦虑与抑郁样行为特征，这与IgCAM表达降低的遗传模型相一致，提示皮层连接缺陷存在因果关系。综上，本研究揭示了一种调控机制，母体的饮食选择若破坏该机制，可能会终身限制后代的大脑功能。