Dataset Information

Dysregulation of Neuronal Genes by Fetal-Neonatal Iron Deficiency Anemia Is Associated with Altered DNA Methylation in the Rat Hippocampus.

ABSTRACT: Early-life iron deficiency results in long-term abnormalities in cognitive function and affective behavior in adulthood. In preclinical models, these effects have been associated with long-term dysregulation of key neuronal genes. While limited evidence suggests histone methylation as an epigenetic mechanism underlying gene dysregulation, the role of DNA methylation remains unknown. To determine whether DNA methylation is a potential mechanism by which early-life iron deficiency induces gene dysregulation, we performed whole genome bisulfite sequencing to identify loci with altered DNA methylation in the postnatal day (P) 15 iron-deficient (ID) rat hippocampus, a time point at which the highest level of hippocampal iron deficiency is concurrent with peak iron demand for axonal and dendritic growth. We identified 229 differentially methylated loci and they were mapped within 108 genes. Among them, 63 and 45 genes showed significantly increased and decreased DNA methylation in the P15 ID hippocampus, respectively. To establish a correlation between differentially methylated loci and gene dysregulation, the methylome data were compared to our published P15 hippocampal transcriptome. Both datasets showed alteration of similar functional networks regulating nervous system development and cell-to-cell signaling that are critical for learning and behavior. Collectively, the present findings support a role for DNA methylation in neural gene dysregulation following early-life iron deficiency.

SUBMITTER: Lien YC

PROVIDER: S-EPMC6566599 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dysregulation of Neuronal Genes by Fetal-Neonatal Iron Deficiency Anemia Is Associated with Altered DNA Methylation in the Rat Hippocampus.

Lien Yu-Chin YC Condon David E DE Georgieff Michael K MK Simmons Rebecca A RA Tran Phu V PV

Nutrients 20190527 5

Early-life iron deficiency results in long-term abnormalities in cognitive function and affective behavior in adulthood. In preclinical models, these effects have been associated with long-term dysregulation of key neuronal genes. While limited evidence suggests histone methylation as an epigenetic mechanism underlying gene dysregulation, the role of DNA methylation remains unknown. To determine whether DNA methylation is a potential mechanism by which early-life iron deficiency induces gene dys ...[more]

PMID: 31137889

Similar Datasets

Project description:Gestational-neonatal iron deficiency, a common micronutrient deficiency affecting the offspring of more than 30% of pregnancies worldwide, leads to long-term cognitive and behavioral abnormalities. Preclinical models of gestational-neonatal iron deficiency result in reduced energy metabolism and expression of genes critical for neuronal plasticity and cognitive function, which are associated with a smaller hippocampal volume and abnormal neuronal dendrite growth. Because insulin-like growth factor (IGF) modulates early postnatal cellular growth, differentiation, and survival, we used a dietary-induced rat model to assess the effects of gestational iron deficiency on activity of the IGF system. We hypothesized that gestational iron deficiency attenuates postnatal hippocampal IGF signaling and results in downstream effects that contribute to hippocampal anatomic and functional deficits. At postnatal day (P) 15 untreated gestational-neonatal iron deficiency markedly suppressed hippocampal IGF activation and protein kinase B signaling, and reduced neurogenesis, while elevating extracellular signal-regulated kinase 1/2 signaling and hypoxia-inducible factor-1? expression. Iron treatment beginning at P7 restored IGF signaling, increased neurogenesis, and normalized all parameters by the end of rapid hippocampal differentiation (P30). Expression of the neuron-specific synaptogenesis marker, disc-large homolog 4 (PSD95), increased more rapidly than the glia-specific myelination marker, myelin basic protein, following iron treatment, suggesting a more robust response to iron therapy in IGF-I-dependent neurons than IGF-II-dependent glia. Collectively, our findings suggest that IGF dysfunction is in part responsible for hippocampal abnormalities in untreated iron deficiency. Early postnatal iron treatment of gestational iron deficiency reactivates the IGF system and promotes neurogenesis and differentiation in the hippocampus during a critical developmental period.

Project description:Background: Iron deficiency (ID) during the fetal-neonatal period results in long-term neurodevelopmental impairments associated with pervasive hippocampal gene dysregulation. Prenatal choline supplementation partially normalizes these effects, suggesting an interaction between iron and choline in hippocampal transcriptome regulation. To understand the regulatory mechanisms, we investigated epigenetic marks of genes that are poised to be activated (ATAC-seq) or repressed (H3K9me3 ChIP-seq) in iron-repleted adult rats having experienced fetal-neonatal ID exposure with or without prenatal choline supplementation. Results: Fetal-neonatal ID was induced by limiting maternal iron intake from gestational day (G) 2 through postnatal day (P) 7. Half of the pregnant dams were given supplemental choline (5.0 g/kg) from G11-18. This resulted in 4 groups at P65 (Iron-sufficient [IS], Formerly Iron-deficient [FID], IS with choline [ISch], and FID with choline [FIDch]). Hippocampi were collected from P65 iron-repleted male offspring and analyzed for chromatin accessibility and H3K9me3 enrichment. 22% and 24% of differentially transcribed genes in FID- and FIDch-groups, respectively, exhibited significant differences in chromatin accessibility, whereas 1.7% and 13% exhibited significant differences in H3K9me3 enrichment. These changes mapped onto gene networks regulating synaptic plasticity, neuroinflammation, and reward circuits. Motif analysis of differentially modified genomic sites revealed significantly stronger choline effects than early-life ID and identified multiple epigenetically modified transcription factor binding sites. Conclusions: This study reveals genome-wide, stable epigenetic changes and epigenetically modifiable gene networks associated with specific chromatin marks in the hippocampus, and lays a foundation to further elucidate iron-dependent epigenetic mechanisms that underlie the long-term effects of fetal-neonatal ID, choline, and their interactions.

Dataset Information

Dysregulation of Neuronal Genes by Fetal-Neonatal Iron Deficiency Anemia Is Associated with Altered DNA Methylation in the Rat Hippocampus.

Publications

Dysregulation of Neuronal Genes by Fetal-Neonatal Iron Deficiency Anemia Is Associated with Altered DNA Methylation in the Rat Hippocampus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure