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Ancestral Folate Promotes Neuronal Regeneration in Serial Generations of Progeny

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Abstract

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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Data Availability

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).

Abbreviations

TSA:

Trichostatin A

DMSO:

Dimethyl sulfoxide vehicle control for TSA

5-azadCyD:

5-Aza-2′-deoxycytidine

FA:

Folic acid

MF:

Methylfolate

S0:

Unbred single generation control

DDI:

Distilled deionized water control

DMR:

Differentially methylated region

HDAC:

Histone deacetylase

DRG:

Dorsal root ganglion

MeDIP:

Methylated DNA immunoprecipitation

MS-PCR:

Methylation-specific PCR

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Author information

NJP designed experiments and performed animal surgery; KJH provided direction and assisted with manuscript writing; ER assisted with experimental design and performed animal surgery; KS performed the in vitro assays; AM analyzed transcription studies and assisted with manuscript writing; SVM assisted in methylation studies and manuscript figures; RA and LB assisted with analysis of transcription studies and manuscript writing; LP performed RNA-Seq experiments; SO performed animal surgery; LRG and KW assisted in animal care, breeding, and surgery; WL performed animal surgery; AB performed animal surgery; NH managed all laboratory activities including molecular and animal studies; TK assisted in animal care, breeding, and surgery; TC performed statistical analyses of in vivo and in vitro studies; SK performed statistical analyses of methylation studies; MAN performed statistical studies related to transgenerational results; and BJI designed experiments, wrote the manuscript, and provided overall direction.

Correspondence to Bermans J. Iskandar.

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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

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Keywords

  • Transgenerational inheritance
  • Central nervous system (CNS)
  • Spinal cord injury
  • Axonal regeneration
  • DNA methylation
  • Epigenetics
  • Folic acid