The Epigenetic Role of Vitamin C in Neurodevelopment

Abstract

The maternal diet during pregnancy is a key determinant of offspring health. Early studies have linked poor maternal nutrition during gestation with a propensity for the development of chronic conditions in offspring. These conditions include cardiovascular disease, type 2 diabetes and even compromised mental health. While multiple factors may contribute to these outcomes, disturbed epigenetic programming during early development is one potential biological mechanism. The epigenome is programmed primarily in utero, and during this time, the developing fetus is highly susceptible to environmental factors such as nutritional insults. During neurodevelopment, epigenetic programming coordinates the formation of primitive central nervous system structures, neurogenesis, and neuroplasticity. Dysregulated epigenetic programming has been implicated in the aetiology of several neurodevelopmental disorders such as Tatton-Brown-Rahman syndrome. Accordingly, there is great interest in determining how maternal nutrient availability in pregnancy might affect the epigenetic status of offspring, and how such influences may present phenotypically. In recent years, a number of epigenetic enzymes that are active during embryonic development have been found to require vitamin C as a cofactor. These enzymes include the ten-eleven translocation methylcytosine dioxygenases (TETs) and the Jumonji C domain-containing histone lysine demethylases that catalyse the oxidative removal of methyl groups on cytosines and histone lysine residues, respectively. These enzymes are integral to epigenetic regulation and have fundamental roles in cellular differentiation, the maintenance of pluripotency and development. The dependence of these enzymes on vitamin C for optimal catalytic activity illustrates a potentially critical contribution of the nutrient during mammalian development. These insights also highlight a potential risk associated with vitamin C insufficiency during pregnancy. The link between vitamin C insufficiency and development is particularly apparent in the context of neurodevelopment and high vitamin C concentrations in the brain are indicative of important functional requirements in this organ. Accordingly, this review considers the evidence for the potential impact of maternal vitamin C status on neurodevelopmental epigenetics.

Keywords: TET enzymes; ascorbate; epigenetic programming; maternal nutrition; neurodevelopment; ten-eleven translocation methylcytosine dioxygenases; vitamin C.

Figure 1

Tissue Distribution of Vitamin C. Vitamin C is present at different concentrations in different tissues. Notably, the concentration of vitamin C is particularly high in the brain and adrenal glands [19], with the newborn retaining higher plasma concentrations of vitamin C that its mother at the time of birth [8]. These observations highlight the importance of understanding the role of vitamin C during neurodevelopment. Figure created with Biorender.com using published data [19].

Figure 2

Changes in DNA Methylation during Mammalian Development. See text above for further details. Figure adapted from the templates library available at Biorender.com accessed on 8 December 2021.

Figure 3

Pathway of DNA Methylation and Demethylation The de novo methylation of cytosine is carried out by DNMT3A and DNMT3B, with methylation being maintained during cell replication by DNMT1. 5-methylcytosine (5mC) is demethylated via two pathways. Passive demethylation occurs due to the failure to maintain methylation after cell division, resulting in the gradual dilution of methylated cytosines. In contrast, the process of active demethylation is catalysed by the TET enzymes (TET1–TET3), which oxidise 5mC to 5-hydoxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). 5fC and 5caC are substrates for thymine–DNA–glycosylase (TDG) which leads to the excision of the oxidised cytosine base. The resulting abasic site is repaired via base excision repair to restore the original cytosine molecule. Figure from Biorender.com.

Figure 4

Schematic of TET Enzyme Expression and Corresponding 5hmC Levels during Neurogenesis. The three Tet enzymes have distinct and important roles in neurodevelopment. Tet1 is highly expressed in embryonic stem cells (ESCs) where it regulates the expression of pluripotency related genes. 5hmC levels in ESCs are correspondingly elevated. The expression of Tet1 decreases progressively during the ESC to neural progenitor cell (NPC) and NPC to neuron transition. Tet2 is basally expressed in all three cell types and is involved in controlling the balance between self-renewal and differentiation. Tet3 expression is negligible in ESCs but increases rapidly during the subsequent differentiation events, promoting the terminal differentiation of neurons. 5hmC levels are the lowest in the NPC population which reflects their partially-differentiated identity and transient state. In contrast, neurons exhibit high levels of 5hmC due to the dynamic nature of neuronal gene expression required for neuroplasticity. Figure created with Biorender.com accessed on 8 December 2021.