Early-Life Iron Deficiency Anemia Programs the Hippocampal Epigenomic Landscape

Abstract

Iron deficiency (ID) anemia is the foremost micronutrient deficiency worldwide, affecting around 40% of pregnant women and young children. ID during the prenatal and early postnatal periods has a pronounced effect on neurodevelopment, resulting in long-term effects such as cognitive impairment and increased risk for neuropsychiatric disorders. Treatment of ID has been complicated as it does not always resolve the long-lasting neurodevelopmental deficits. In animal models, developmental ID results in abnormal hippocampal structure and function associated with dysregulation of genes involved in neurotransmission and synaptic plasticity. Dysregulation of these genes is a likely proximate cause of the life-long deficits that follow developmental ID. However, a direct functional link between iron and gene dysregulation has yet to be elucidated. Iron-dependent epigenetic modifications are one mechanism by which ID could alter gene expression across the lifespan. The jumonji and AT-rich interaction domain-containing (JARID) protein and the Ten-Eleven Translocation (TET) proteins are two families of iron-dependent epigenetic modifiers that play critical roles during neural development by establishing proper gene regulation during critical periods of brain development. Therefore, JARIDs and TETs can contribute to the iron-mediated epigenetic mechanisms by which early-life ID directly causes stable changes in gene regulation across the life span.

Keywords: JARIDs; TETs; cognition; epigenetics; neurodevelopment; perinatal iron deficiency.

Figure 1

Iron-dependent Ten-Eleven Translocation (TET) proteins influence the epigenetic modifications of DNA methylation and hydroxymethylation. (A) Covalently modified cytosine bases are a major class of epigenetic modification. 5-methylcytosine (5mC) can be maintained long-term as a stable epigenetic modification or hydroxylated by the iron-dependent TET methylcytosine dioxygenases to 5-hydroxymethylcytosine (5hmC). 5hmC can serve as a stable epigenetic modification or an intermediate in the active DNA demethylation pathway, which reverses modified cytosines to unmodified states by serial modifications mediated in by TETs and thymine DNA glycosylase (TDG). (B) Expression of TET dioxygenases in the adult mouse brain. All three TET are highly expressed in the mouse hippocampus (HC) and cerebellum (CB). Images modified from Allen Mouse Brain Atlas [67].

Figure 2

Iron-dependent jumonji and AT-rich interaction domain-containing (JARID) histone demethylase. (A) Illustration showing domains within JARID polypeptide. The Jumonji C (JmjC) domain is illustrated by 3D-modeling showing the iron (red) binding pocket with the co-factor alpha-ketoglutarate (blue). Image adapted from Klose, Kallin, and Zhang, Nature Reviews Genetics, 2006 [82]. (B) Major histone methylation sites within histone H3. Illustration depicting specific lysine (K) residues with histone demethylases (JARID/KDM). Enrichment of methylated K4 and K36 (blue) is associated with active transcription, whereas enrichment of methylated K9 and K27 (red) is associated with gene silencing (Adapted from Pedersen and Helin, 2010 [71]).

Figure 3

Effects of early-life iron deficiency (ID) anemia on the rat hippocampus. Illustration depicting the effects on early-life ID anemia on hippocampal structure and gene expression. Abnormal structure development, inappropriate gene expression, and their interaction are contributing factors to the abnormal hippocampal function in adult rats that were iron-deficient during fetal and neonatal life.