Placenta insufficiency caused by abnormal folate metabolism linked to fetal growth restriction across gestation and generations [RNA-Seq]

Folate is important for fetal development and growth, yet its role in placentation is understudied. Here we report that disrupting folate metabolism by the hypomorphic Mtrr mutation in mice causes morphological and functional defects in their placentas that correspond with early- and late-onset fetal growth restriction. Remarkably, Mtrr heterozygous males initiate inheritance of similar placenta phenotypes and fetal growth defects in their wildtype grandprogeny. An integrated genome-wide approach shows placental transcriptional change and epigenetic instability is caused by an intrinsic or ancestral Mtrr mutation, affecting genes important for placenta development and function (e.g., pregnancy specific glycoprotein (Psg)/Ceacams). Crucially, we establish a functional association between mouse placenta transcript levels and fetal size and identify a human PSG gene variant linked to birthweight. This study provides molecular insight into how folate metabolism influences placental development and attributes a potential multigenerational epigenetic mechanism to unexplained cases of fetal growth defects. RNA-seq from E10.5 mouse placentas to assess the intrinsic and ancestral effect of an Mtrr<gt> allele impairing folate metabolism叶酸对胎儿发育与生长至关重要，但其在胎盘形成中的作用尚未得到充分研究。本研究报道，小鼠中低功能型Mtrr突变破坏叶酸代谢，会导致胎盘出现形态与功能缺陷，并伴随早发性及晚发性胎儿生长受限。值得注意的是，Mtrr杂合雄性小鼠可将类似的胎盘表型与胎儿生长缺陷传递给其野生型孙辈。整合全基因组分析方法显示，内源或祖辈携带的Mtrr突变会引发胎盘转录组改变与表观遗传不稳定性，进而影响胎盘发育与功能相关的关键基因（如妊娠特异性糖蛋白（Pregnancy Specific Glycoprotein, Psg）/CEACAMs）。至关重要的是，本研究明确了小鼠胎盘转录水平与胎儿体型之间的功能关联，并鉴定出一个与出生体重相关的人类PSG基因变异。本研究为叶酸代谢如何影响胎盘发育提供了分子层面的见解，并将未明确病因的胎儿生长缺陷病例归因于一种潜在的多代表观遗传机制。本研究通过对胚胎第10.5天（E10.5）小鼠胎盘进行RNA测序，以评估损害叶酸代谢的Mtrr<gt>等位基因的内源效应与祖辈传递效应。