Folate supplementation in F0 mating rodents increases regeneration of injured spinal axons in vivo in 4 or more 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 differential patterns of genomic DNA methylation and RNA transcription in treated lineages. Enhanced axonal regeneration phenotypes are observed with diverse folate preparations and routes of administration, in outbred and inbred rodent strains, and in two rodent genera comprising rats and mice, and are reversed in F4–F5 progeny by pretreatment with DNA demethylating agents prior to phenotyping. Uniform transmission of the enhanced regeneration phenotype to progeny together with differential patterns of DNA methylation and RNA expression is consistent with 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.
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All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Likelihood-based calculations performed using R language source code are available at www.biostat.wisc.edu/~ngroup/benny/. The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus (Edgar et al., 2002) and are accessible through GEO Series accession number GSE137643 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE137643).
Dimethyl sulfoxide vehicle control for TSA
Unbred single generation control
Distilled deionized water control
Differentially methylated region
Dorsal root ganglion
Methylated DNA immunoprecipitation
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Thomas Kuehn passed away during the preparation of this study.
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Patel, N.J., Hogan, K.J., Rizk, E. et al. Ancestral Folate Promotes Neuronal Regeneration in Serial Generations of Progeny. Mol Neurobiol (2020). https://doi.org/10.1007/s12035-019-01812-5
- Transgenerational inheritance
- Central nervous system (CNS)
- Spinal cord injury
- Axonal regeneration
- DNA methylation
- Folic acid