Ancestral folate promotes neuronal regeneration in serial generations of progeny [RNA-seq]

Folate supplementation in F0 mating rodents increases regeneration of injured spinal axons in vivo in at least 4 generations of progeny (F1-F4) in the absence of interval folate administration to the progeny. Transmission of the enhanced regeneration phenotype to untreated progeny parallels axonal growth in neuron culture after in vivo folate administration to the F0 ancestors alone, in correlation with transformed patterns of genomic DNA methylation and gene expression in treated lineages. Enhanced axonal regeneration phenotypes are observed with diverse folate preparations and routes of administration, in outbred and inbred rodent strains, in distinct rodent genera, and are reversed in F4-F5 progeny by pretreatment with DNA demethylating agents prior to phenotyping. Uniform transmission of the phenotype to progeny suggests a non-Mendelian mechanism. The capacity of an essential nutritional co-factor to induce a beneficial transgenerational phenotype in untreated offspring carries broad implications for the diagnosis, prevention, and treatment of inborn and acquired disorders.对交配期亲代0代（F0）啮齿类动物补充叶酸（folate supplementation），可在无需对子代进行间歇性叶酸给药的条件下，促使至少4个子代世代（F1至F4）的受损脊髓轴突在体内（in vivo）实现再生。该增强的轴突再生表型向未给药子代的传递规律，与仅对F0亲代进行体内叶酸给药后神经元培养物中的轴突生长特征高度吻合，且与处理谱系内基因组DNA甲基化（genomic DNA methylation）与基因表达（gene expression）的模式改变显著相关。在远交系与近交系啮齿类品系、不同啮齿类属中，使用多种叶酸制剂及给药途径均可观测到轴突再生增强的表型；且在表型鉴定前经DNA去甲基化试剂（DNA demethylating agents）预处理，可逆转F4至F5子代中的该表型。该表型向子代的稳定传递提示其遵循非孟德尔遗传（non-Mendelian）机制。一种必需营养辅因子可在未给药子代中诱导出有益的跨代表型（transgenerational phenotype），这一发现对先天性与获得性疾病的诊断、预防及治疗具有广泛的研究与应用启示。