Biology subjects

Georgieff, M. K.

Publications and source records attributed to Georgieff, M. K..

3 recordsLinked to original sources

bioRxiv2023

Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons

BackgroundDeveloping neurons have high thyroid hormone and iron requirements to support their metabolism and growth. Early-life iron and thyroid hormone deficiencies are prevalent, often coexist, and increase the risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid hormone levels and impairs thyroid hormone-responsive gene expression in the neonatal rat brain. ObjectiveThis study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons. MethodsIron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 days in vitro (DIV). At 11DIV and 18DIV, mRNA levels for thyroid hormone-regulated genes indexing thyroid hormone homeostasis (Hr, Crym, Dio2, Slco1c1, Slc16a2) and neurodevelopment (Nrgn, Pvalb, Klf9) were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures and gene expression and ATP levels were quantified at 21DIV. ResultsAt 11DIV and 18DIV, neuronal iron deficiency decreased Nrgn, Pvalb, and Crym, and by 18DIV, Slc16a2, Slco1c1, Dio2, and Hr were increased; collectively suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal Component Analysis (PCA) reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status (Tfr1 mRNA). Iron repletion from 14-21DIV restored neurodevelopmental genes, but not all thyroid hormone homeostatic genes, and ATP concentrations remained significantly altered. PCA clustering suggests that cultures replete with iron maintain a gene expression signature indicative of previous iron deficiency. ConclusionsThese novel findings suggest there is an intracellular mechanism coordinating cellular iron/thyroid hormone activities. We speculate this is a part of homeostatic response to match neuronal energy production and growth signaling for these important metabolic regulators. However, iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency.

neuroscience↗

bioRxiv2022

Sex-Specific Effects of Early-Life Iron Deficiency and Prenatal Choline Treatment on Adult Rat Hippocampal Transcriptome

BackgroundFetal-neonatal iron deficiency (ID) causes long-term neurocognitive and affective dysfunctions. Clinical and preclinical studies have shown that early-life ID produces sex-specific effects. However, little is known about the molecular mechanisms underlying these early-life ID-induced sex-specific effects on neural gene regulation. ObjectiveTo illustrate sex-specific transcriptome alteration in adult rat hippocampus induced by fetal-neonatal ID and prenatal choline treatment. MethodsPregnant rats were fed an iron-deficient (4 mg/kg Fe) or iron-sufficient (200 mg/kg Fe) diet from gestational day (G) 2 to postnatal day (P) 7 with or without choline supplementation (5 g/kg choline) from G11-18. Hippocampi were collected from P65 offspring of both sexes and analyzed for changes in gene expression. ResultsBoth early-life ID and choline treatment induced transcriptional changes in adult female and male rat hippocampus. Both sexes showed ID-induced alterations in gene networks leading to enhanced neuroinflammation. In females, ID-induced changes indicating enhanced activity of oxidative phosphorylation and fatty acid metabolism, which are contrary to the ID effect in males. Prenatal choline supplementation induced the most robust changes in gene expression, particularly in the iron-deficient animals where it partially rescued ID-induced dysregulations. Choline supplementation also altered hippocampal transcriptome in the iron-sufficient rats with indications for both beneficial and adverse effects. ConclusionsThis study provided unbiased global assessments of gene expression regulated by iron and choline status in a sex-specific manner, with greater effects in female than male rats. Our new findings highlight potential sex-specific gene networks regulated by iron and choline status for further investigation.

neuroscience↗

bioRxiv2022

ATAC and histone H3K9me3 landscapes revealed the altered epigenome by fetal-neonatal iron deficiency in the adult male rat hippocampus

Iron deficiency during the fetal-neonatal period results in long-term neurodevelopmental impairments associated with pervasive and widespread hippocampal gene dysregulation. Globally, fetal-neonatal iron deficiency produces both long-term activation and repression of hundreds of loci in the adult rat hippocampus. Prenatal choline (a methyl donor) supplementation can partially reverse these effects, suggesting an interaction between iron and choline in regulating the hippocampal transcriptome. To gain insights into the underlying epigenetic signatures, we integrate hippocampal transcriptomes and epigenetic marks of active (transposase accessible chromatin/ATAC) and repressed (H3K9me3 enrichment) genes in adult rats that had been exposed to fetal-neonatal iron deficiency with or without prenatal choline supplementation. Rats were made iron-deficient during fetal and neonatal period by limiting maternal iron intake from gestational day (G) 2 through postnatal day (P) 7. Choline (5.5 g/kg) was given to half of the pregnant dams during G11-18. This paradigm produced four comparison groups (Iron-sufficient [IS], Iron-deficient [ID], IS+choline [ISch], and ID+choline [IDch]). Hippocampi were collected from P65 males and analyzed for changes in chromatin conformation and histone H3K9me3 enrichment. ATAC-seq results accounted for 22% and 24%, whereas H3K9me3 enrichment accounted for 1.7% and 13% of differences in ID- and IDch-altered gene expression. These epigenetic changes were annotated onto gene networks regulating synaptic structure and plasticity, neuroinflammation, and reward circuits. The low correlation between gene dysregulation and changes in ATAC or H3K9me3 signatures indicate involvements of other epigenetic modifications. This study provides a genome-wide findings of stable epigenetic changes and lays a foundation for further analyses to elucidate more fully iron-dependent epigenetic mechanisms that underlie iron deficiency, choline supplementation, and their interactions in mediating long-term neural gene dysregulation. SIGNIFICANCE STATEMENTEarly-life iron deficiency can lead to long-term neurocognitive dysfunction and persistent neural gene dysregulation, despite prompt iron replenishment, suggesting that iron deficiency results in long-term neuroepigenomic changes. This study combined RNA-seq, ATAC-seq, and ChIP-seq to provide the epigenetic basis for gene dysregulation due to fetal-neonatal iron deficiency and prenatal choline supplementation. We found that early-life iron deficiency alters epigenetic regulation of genes involved in neuronal development, cell signaling, neuroinflammation, and reward-related cognition. While choline supplementation to iron-deficient animals partially reverses these effects, it also leads to dysregulation of genes in iron-sufficient animals. The patterns of gene dysregulation were positively correlated with differences in chromatin accessibility and negatively correlated with repressive histone H3K9me3 modification. Our results indicate that these changes at the epigenetic level partially account for the long-term hippocampal gene dysregulation.

neuroscience↗