BDNF Val66Met基因型与雌二醇反向添加的跨物种模型中的经前焦虑障碍转录组的表观遗传相交

Epigenetic intersection of BDNF Val66Met genotype with premenstrual dysphoric disorder transcriptome in a cross-species model of estradiol add-back

BDNF：脑源性神经营养因子

Premenstrual dysphoric disorder (PMDD) affects over 5% of women, with symptoms similar to anxiety and major depression, and is associated with differential sensitivity to circulating ovarian hormones. Little is known about the genetic and epigenetic factors that increase the risk to develop PMDD. We report that 17β-estradiol (E2) affects the behavior and the epigenome in a mouse model carrying a single-nucleotide polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met), in a way that recapitulates the hallmarks of PMDD. Ovariectomized mice heterozygous for the BDNF Met allele (Het-Met) and their matched wild-type (WT) mice were administered estradiol or vehicle in drinking water for 6 weeks. Using the open field and the splash test, we show that E2 add-back induces anxiety-like and depression-like behavior in Het-Met mice, but not in WT mice. RNA-seq of the ventral hippocampus (vHpc) highlights that E2-dependent gene expression is markedly different between WT mice and Het-Met mice. Through a comparative whole-genome RNA-seq analysis between mouse vHpc and lymphoblastoid cell line cultures from control women and women with PMDD, we discovered common epigenetic biomarkers that transcend species and cell types. Those genes include epigenetic modifiers of the ESC/E(Z) complex, an effector of response to ovarian steroids. Although the BDNF Met genotype intersects the behavioral and transcriptional traits of women with PMDD, we suggest that these similarities speak to the epigenetic factors by which ovarian steroids produce negative behavioral effects.

经前焦虑障碍（PMDD）影响超过5%的女性，症状类似于焦虑和重度抑郁，并与对循环卵巢激素的不同敏感性有关。很少有人知道遗传和表观遗传因素会增加患PMDD的风险。我们报告了17β-雌二醇（E2）影响小鼠模型的行为和表观基因组，该模型携带了脑源性神经营养因子基因（BDNF Val66Met）的单核苷酸多态性，以一种概括PMDD特征的方式。将BDNF Met等位基因（Het-Met）杂合的卵巢切除小鼠及其匹配的野生型（WT）小鼠在饮用水中给予雌二醇或载体6周。使用开放场和飞溅测试，我们显示反向添加E2诱导Het-Met小鼠中的焦虑样和抑郁样行为，但在WT小鼠中没有。腹侧海马区（vHpc）的转录组测序突出显示E2依赖的基因表达在WT小鼠和Het-Met小鼠之间明显不同。通过比较对照组和PMDD组小鼠腹侧海马区和淋巴母细胞系培养的全基因组RNA-seq分析，我们发现了超越物种和细胞类型的常见表观遗传生物标志物。这些基因包括ESC / E（Z）复合物的表观遗传修饰物，这是一种对卵巢类固醇反应的效应物。 尽管BDNF Met基因型与PMDD女性的行为和转录特征相交，但我们认为这些相似性与卵巢类固醇产生负面行为影响的表观遗传因素有关。

2018 Oct 24 发表于Mol Psychiatry（IF11.973）