Impact of neonatal iron deficiency on hippocampal DNA methylation and gene transcription in a porcine biomedical model of cognitive development.
Iron deficiency is a common childhood micronutrient deficiency that results in altered hippocampal function and cognitive disorders. However, little is known about the mechanisms through which neonatal iron deficiency results in long lasting alterations in hippocampal gene expression and function. DNA methylation is an epigenetic mark involved in gene regulation and altered by environmental factors. In this study, hippocampal DNA methylation and gene expression were assessed via reduced representation bisulfite sequencing and RNA-seq on samples from a previous study reporting reduced hippocampal-based learning and memory in a porcine biomedical model of neonatal iron deficiency.



In total 192 differentially expressed genes (DEGs) were identified between the iron deficient and control groups. GO term and pathway enrichment analysis identified DEGs associated with hypoxia, angiogenesis, increased blood brain barrier (BBB) permeability, and altered neurodevelopment and function. Of particular interest are genes previously implicated in cognitive deficits and behavioral disorders in humans and mice, including HTR2A, HTR2C, PAK3, PRSS12, and NETO1. Altered genome-wide DNA methylation was observed across 0.5 million CpG and 2.4 million non-CpG sites. In total 853 differentially methylated (DM) CpG and 99 DM non-CpG sites were identified between groups. Samples clustered by group when comparing DM non-CpG sites, suggesting high conservation of non-CpG methylation in response to neonatal environment. In total 12 DM sites were associated with 9 DEGs, including genes involved in angiogenesis, neurodevelopment, and neuronal function.



Neonatal iron deficiency leads to altered hippocampal DNA methylation and gene regulation involved in hypoxia, angiogenesis, increased BBB permeability, and altered neurodevelopment and function. Together, these results provide new insights into the mechanisms through which neonatal iron deficiency results in long lasting reductions in cognitive development in humans.
Department of Animal Sciences, University of Illinois, 1201 W Gregory Drive, Urbana, IL, 61801, USA.|Animal Breeding and Genomics Centre, Wageningen University, P.O. Box 338, Wageningen, 6700AH, The Netherlands.
Kyle M
KM
Schachtschneider
Department of Animal Sciences, University of Illinois, 1201 W Gregory Drive, Urbana, IL, 61801, USA.|College of Animal Science and Technology, Sichuan Agricultural University, Wenjiang, Huimin Road #221, Chengdu, 610000, China.
Yingkai
Y
Liu
Department of Animal Sciences, University of Illinois, 1201 W Gregory Drive, Urbana, IL, 61801, USA.
Laurie A
LA
Rund
Animal Breeding and Genomics Centre, Wageningen University, P.O. Box 338, Wageningen, 6700AH, The Netherlands.
Ole
O
Madsen
Department of Animal Sciences, University of Illinois, 1201 W Gregory Drive, Urbana, IL, 61801, USA.
Rodney W
RW
Johnson
Animal Breeding and Genomics Centre, Wageningen University, P.O. Box 338, Wageningen, 6700AH, The Netherlands.
Martien A M
MA
Groenen
Department of Animal Sciences, University of Illinois, 1201 W Gregory Drive, Urbana, IL, 61801, USA. schook@illinois.edu.|Institute for Genomic Biology, University of Illinois, 1206 W Gregory Drive, Urbana, IL, 61801, USA. schook@illinois.edu.
Lawrence B
LB
Schook
D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000378:metabolism; D016000:Cluster Analysis; D003071:Cognition / Q000502:physiology*; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing; D006624:Hippocampus / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D000090463:Iron Deficiencies; D018919:Neovascularization, Physiologic; D055495:Neurogenesis / Q000235:genetics; D010539:Permeability; D010641:Phenotype; D013552:Swine; D014158:Transcription, Genetic
D007501:Iron
Angiogenesis; DNA methylation; Gene expression; Hypoxia; Neonatal iron deficiency; Neurodevelopment; Porcine biomedical model; RNA-seq; RRBS