Gestational Choline Supply Regulates Methylation of Histone H3, Expression of Histone Methyltransferases G9a (Kmt1c) and Suv39h1 (Kmt1a), and DNA Methylation of Their Genes in Rat Fetal Liver and Brain

Abstract

Choline is an essential nutrient that, via its metabolite betaine, serves as a donor of methyl groups used in fetal development to establish the epigenetic DNA and histone methylation patterns. Supplementation with choline during embryonic days (E) 11-17 in rats improves memory performance in adulthood and protects against age-related memory decline, whereas choline deficiency impairs certain cognitive functions. We previously reported that global and gene-specific DNA methylation increased in choline-deficient fetal brain and liver, and these changes in DNA methylation correlated with an apparently compensatory up-regulation of the expression of DNA methyltransferase Dnmt1. In the current study, pregnant rats were fed a diet containing varying amounts of choline (mmol/kg: 0 (deficient), 8 (control), or 36 (supplemented)) during E11-17, and indices of histone methylation were assessed in liver and frontal cortex on E17. The mRNA and protein expression of histone methyltransferases G9a and Suv39h1 were directly related to the availability of choline. DNA methylation of the G9a and Suv39h1 genes was up-regulated by choline deficiency, suggesting that the expression of these enzymes is under negative control by methylation of their genes. The levels of H3K9Me2 and H3K27Me3, tags of transcriptionally repressed chromatin, were up-regulated by choline supplementation, whereas the levels of H3K4Me2, associated with active promoters, were highest in choline-deficient rats. These data show that maternal choline supply during pregnancy modifies fetal histone and DNA methylation, suggesting that a concerted epigenomic mechanism contributes to the long term developmental effects of varied choline intake in utero.Choline is an essential nutrient whose adequate supply in maternal diet during pregnancy is vital for normal development of the fetus (1), and studies in humans (2) and animals (3-6) indicate that its intake during gestation is especially important for the normal development and function of the central nervous system. For example, in a model that employs offspring of pregnant rats or mice consuming diets of varying choline content during only a 1-week period of the second half of gestation (E11-17), 2 choline deficiency causes impairments in certain memory tasks (7), whereas choline supplementation improves memory and attention (7-14) and, remarkably, prevents agerelated memory decline (3,5,14). In addition to behavioral changes, altered choline availability modifies fetal hippocampal cell proliferation (15, 16), apoptosis (17), and differentiation (18,19). High E11-17 choline intake increases the size of cholinergic neurons in the adult basal forebrain (20) and enhances acetylcholine storage (14) and release (21), elevates brain concentrations of the neurotrophins nerve growth factor, brainderived neurotrophic factor, and NT3 (22-24) and of IGF2 and its receptor IGF2R (25), lowers the stimulation threshold for induction of long term potentiation (26, 27), and enhances depolarization-induced mitogen-activated protei...

Maternal Nutrition and Epigenetic Perturbation: Modeling Trends to Translation

“…DNA methylation changes at Cdkn3 (a cell proliferation inhibitor) was correlated with protein levels and is consistent with previous findings of reduced cell proliferation within the Ammon's horn associated with choline deficiency [30,31]. In a separate study using rat models, choline availability through enrichment or deficiency between E11 and E17 was linked to DNA methylation changes at histone methyltransferase genes, G9a and Suv39h1 in E17 liver [32]. These changes were correlated with RNA and protein expression levels at these loci as well as levels of active (H3K4me2) and repressive (H3K27me3 and H3K9me2) histone modifications.…”

Changes in Methionine Metabolism and Histone H3 Trimethylation Are Linked to Mitochondrial Defects in Multiple Sclerosis

“…Decreased cystathionine in MS is indicative of an imbalance in redox homeostasis and is consistent with studies demonstrating increased oxidative damage in the MS brain due to activated microglial derived NO and ROS (Gilgun-Sherki et al, 2004;Gonsette, 2008;Pandit et al, 2009). We also found reductions in levels of mitochondrial electron transport chain complexes and decreased concentrations of the neuronal mitochondrial metabolite NAA, which is linked to ATP production and mitochondrial oxidative phosphorylation (Clark, 1998;Li et al, 2013), in MS samples. NAA levels were found to be correlated with cystathionine concentration, suggesting that there is a relationship between dysregulation of redox homeostasis and neuronal respiratory capacity in MS.…”

Histone H3K9 modifications are a local chromatin event involved in ethanol-induced neuroadaptation of the NR2B gene

“…Our present study presents the possibility that DNA and histone methylation may have a mutually reinforcing relationship in the formation of the long-lasting effect that ethanol and other abused drugs cause. 71 Based on the finding of this study, we propose the following mechanistic model: CIE treatment and removal initially induces the downregulation of a set of HMTs (e.g., G9a, Suv39 h1 and others observed in this study), although the impact of some of the other enzymes on the actions of ethanol has not yet been determined. The downregulation results in reduced methylation of H3K9 lysine residue.…”