title: Maternal vitamin D depletion alters DNA methylation at imprinted loci in multiple generations.
abstract: Environmental perturbation of epigenetic mechanisms is linked to a growing number of diseases. Characterizing the role environmental factors play in modifying the epigenome is important for disease etiology. Vitamin D is an essential nutrient affecting brain, bone, heart, immune and reproductive health. Vitamin D insufficiency is a global issue, and the role in maternal and child health remains under investigation.
  
  
  
  We used Collaborative Cross (CC) inbred mice to characterize the effect of maternal vitamin D depletion on offspring phenotypic and epigenetic outcomes at imprinted domains (H19/Igf2,Snrpn,Dlk1/Gtl2, andGrb10) in the soma (liver) and germline (sperm). We assessed outcomes in two generations of offspring to determine heritability. We used reciprocal crosses between lines CC001/Unc and CC011/Unc to investigate parent of origin effects.
  
  
  
  Maternal vitamin D deficiency led to altered body weight and DNA methylation in two generations of offspring. Loci assayed in adult liver and sperm were mostly hypomethylated, but changes were few and small in effect size (<7 % difference on average). There was no change in total expression of genes adjacent to methylation changes in neonatal liver. Methylation changes were cell type specific such that changes atIG-DMRwere present in sperm but not in liver. Some methylation changes were distinct between generations such that methylation changes at theH19ICRin second-generation liver were not present in first-generation sperm or liver. Interestingly, some diet-dependent changes in body weight and methylation were seemingly influenced by parent of origin such that reciprocal crosses exhibited inverse effects.
  
  
  
  These findings demonstrate that maternal vitamin D status plays a role in determining DNA methylation state in the germline and soma. Detection of methylation changes in the unexposed second-generation demonstrates that maternal vitamin D depletion can have long-term effects on the epigenome of subsequent generations. Differences in vitamin D-dependent epigenetic state between cell types and generations indicate perturbation of the epigenetic landscape rather than a targeted, locus-specific effect. While the biological importance of these subtle changes remains unclear, they warrant an investigation of epigenome-wide effects of maternal vitamin D depletion.
authors: Nutrition Research Institute, University of North Carolina, Kannapolis, NC 28081 USA.
authors: Jing
authors: J
authors: Xue
authors: Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599 USA ; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC 27599 USA.
authors: Sarah A
authors: SA
authors: Schoenrock
authors: Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599 USA ; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599 USA.
authors: William
authors: W
authors: Valdar
authors: Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599 USA ; Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599 USA.
authors: Lisa M
authors: LM
authors: Tarantino
authors: Nutrition Research Institute, University of North Carolina, Kannapolis, NC 28081 USA ; Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599 USA ; Department of Nutrition, Gillings School of Public Health, University of North Carolina, Chapel Hill, NC 27599 USA.
authors: Folami Y
authors: FY
authors: Ideraabdullah
mesh_terms: D000818:Animals; D001835:Body Weight; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D008099:Liver / Q000737:chemistry*; D008297:Male; D051379:Mice; D009035:Mothers; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics*; D013094:Spermatozoa / Q000737:chemistry*; D014808:Vitamin D Deficiency / Q000235:genetics*
keywords: Collaborative Cross; Epigenetic inheritance; Imprinting; Maternal diet; Parent of origin; Vitamin D