PMID- 25519736 OWN - NLM STAT- MEDLINE DCOM- 20150409 LR - 20211203 IS - 1522-1490 (Electronic) IS - 0363-6119 (Print) IS - 0363-6119 (Linking) VI - 308 IP - 4 DP - 2015 Feb 15 TI - Fetal iron deficiency induces chromatin remodeling at the Bdnf locus in adult rat hippocampus. PG - R276-82 LID - 10.1152/ajpregu.00429.2014 [doi] AB - 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. CI - Copyright (c) 2015 the American Physiological Society. FAU - Tran, Phu V AU - Tran PV AD - Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; Center for Neurobehavioral Development, University of Minnesota, Minneapolis, Minnesota; tranx271@umn.edu. FAU - Kennedy, Bruce C AU - Kennedy BC AD - Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota; and. FAU - Lien, Yu-Chin AU - Lien YC AD - Children's Hospital Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania. FAU - Simmons, Rebecca A AU - Simmons RA AD - Children's Hospital Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania. FAU - Georgieff, Michael K AU - Georgieff MK AD - 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. LA - eng GR - R01 HD029421/HD/NICHD NIH HHS/United States GR - T32 DA007097/DA/NIDA NIH HHS/United States GR - R01-HD29421-17/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20141217 PL - United States TA - Am J Physiol Regul Integr Comp Physiol JT - American journal of physiology. Regulatory, integrative and comparative physiology JID - 100901230 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Histones) RN - 0 (Upstream Stimulatory Factors) RN - 0 (Usf1 protein, rat) RN - E1UOL152H7 (Iron) RN - EC 2.7.7.- (RNA Polymerase II) RN - EC 3.5.1.98 (Hdac1 protein, rat) RN - EC 3.5.1.98 (Histone Deacetylase 1) RN - N91BDP6H0X (Choline) SB - IM MH - Age Factors MH - Animals MH - Binding Sites MH - Brain-Derived Neurotrophic Factor/*genetics/metabolism MH - Choline/administration & dosage MH - *Chromatin Assembly and Disassembly/drug effects MH - *DNA Methylation/drug effects MH - Disease Models, Animal MH - Down-Regulation MH - *Epigenesis, Genetic/drug effects MH - Female MH - Gestational Age MH - Hippocampus/drug effects/*metabolism MH - Histone Deacetylase 1/metabolism MH - Histones/metabolism MH - Iron/blood MH - *Iron Deficiencies MH - Iron Metabolism Disorders/blood/complications/drug therapy/*genetics MH - Methylation MH - Pregnancy MH - *Prenatal Exposure Delayed Effects MH - Promoter Regions, Genetic MH - RNA Polymerase II/metabolism MH - Rats, Sprague-Dawley MH - Time Factors MH - Upstream Stimulatory Factors/metabolism PMC - PMC4329464 OTO - NOTNLM OT - DNA methylation OT - epigenetics OT - hippocampus OT - histone methylation OT - iron deficiency EDAT- 2014/12/19 06:00 MHDA- 2015/04/10 06:00 PMCR- 2016/02/15 CRDT- 2014/12/19 06:00 PHST- 2014/12/19 06:00 [entrez] PHST- 2014/12/19 06:00 [pubmed] PHST- 2015/04/10 06:00 [medline] PHST- 2016/02/15 00:00 [pmc-release] AID - ajpregu.00429.2014 [pii] AID - R-00429-2014 [pii] AID - 10.1152/ajpregu.00429.2014 [doi] PST - ppublish SO - Am J Physiol Regul Integr Comp Physiol. 2015 Feb 15;308(4):R276-82. doi: 10.1152/ajpregu.00429.2014. Epub 2014 Dec 17.