title: Fetal iron deficiency induces chromatin remodeling at the Bdnf locus in adult rat hippocampus.
abstract: Fetal and subsequent early postnatal iron deficiency causes persistent impairments in cognitive and affective behaviors despite prompt postnatal iron repletion. The long-term cognitive impacts are accompanied by persistent downregulation of brain-derived neurotrophic factor (BDNF), a factor critical for hippocampal plasticity across the life span. This study determined whether early-life iron deficiency epigenetically modifies the Bdnf locus and whether dietary choline supplementation during late gestation reverses these modifications. DNA methylation and histone modifications were assessed at the Bdnf-IV promoter in the hippocampus of rats [at postnatal day (PND) 65] that were iron-deficient (ID) during the fetal-neonatal period. Iron deficiency was induced in rat pups by providing pregnant and nursing dams an ID diet (4 mg/kg Fe) from gestational day (G) 2 through PND7, after which iron deficiency was treated with an iron-sufficient (IS) diet (200 mg/kg Fe). This paradigm resulted in about 60% hippocampal iron loss on PND15 with complete recovery by PND65. For choline supplementation, pregnant rat dams were given dietary choline (5 g/kg) from G11 through G18. DNA methylation was determined by quantitative sequencing of bisulfite-treated DNA, revealing a small alteration at the Bdnf-IV promoter. Chromatin immunoprecipitation analysis showed increased HDAC1 binding accompanied by reduced binding of RNA polymerase II and USF1 at the Bdnf-IV promoter in formerly ID rats. These changes were correlated with altered histone methylations. Prenatal choline supplementation reverses these epigenetic modifications. Collectively, the findings identify epigenetic modifications as a potential mechanism to explicate the long-term repression of Bdnf following fetal and early postnatal iron deficiency.
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; Center for Neurobehavioral Development, University of Minnesota, Minneapolis, Minnesota; tranx271@umn.edu.
authors.forename: Phu V
authors.initials: PV
authors.lastname: Tran
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota; and.
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Kennedy
authors.affiliation: Children's Hospital Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Lien
authors.affiliation: Children's Hospital Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Simmons
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; Center for Neurobehavioral Development, University of Minnesota, Minneapolis, Minnesota; Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota; and.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Georgieff
mesh_terms: D000367:Age Factors; D000818:Animals; D001665:Binding Sites; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D002794:Choline / Q000008:administration & dosage; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D005865:Gestational Age; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D007501:Iron / Q000097:blood; D000090463:Iron Deficiencies; D019189:Iron Metabolism Disorders / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D008745:Methylation; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D051720:Upstream Stimulatory Factors / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D006657:Histones; D051720:Upstream Stimulatory Factors; C497182:Usf1 protein, rat; D007501:Iron; D012319:RNA Polymerase II; C515890:Hdac1 protein, rat; D056284:Histone Deacetylase 1; D002794:Choline
keywords: DNA methylation; epigenetics; hippocampus; histone methylation; iron deficiency