This topic involves the effects of a nutrient (vitamin C) on the genome, on the epigenome in particular — in the developing embryo; hence, this fits well the GEITP’s gene-environment interactions theme. Authors [see attached article] wished to determine the role of vitamin C (ascorbic acid) in the developing germline of the mouse, which is known to express high levels of ascorbate transporters. Authors used Gulo(−/−) knockout mice [the mouse Gulo gene encodes gulonolactone (L-)oxidase; recall that in humans the GULOP pseudogene is nonfunctional, which is why humans (and other primates; also guinea pigs, capybaras, fruit-eating bats, and some birds, fish, insects and reptiles) must have dietary vitamin C to survive] having a green fluorescent protein (GFP) marker to light up early-embryonic stem cells that express Pou5f1 (Oct4) — in order to test the role of vitamin C during germline development.
Embryonic day(E)13.5 was chosen because it represents the lowest point of global DNA methylation during germline reprogramming
[recall that epigenetic effects include DNA-methylation, RNA-interference, histone modifications, and chromatin remodeling]. Vitamin C was removed from the drinking water of female mice — from before mating to E13.5 [authors chose female germ cells because they enter meiosis (cell division that results in four daughter cells, each with half the number of chromosomes of the parent cell) at E13.5, whereas in male germ cells this occurs only postnatally). The withdrawal of vitamin C in this model is compatible with normal development to E13.5; however, there was a significant decrease in the number of primordial germ cells (PGCs) in vitamin C-deficient female embryos, compared with controls.
The embryonic germline is of particular interest because of its potential for inter- and trans-generational epigenetic effects. The mammalian germline undergoes extensive DNA-demethylation — which occurs largely by passive dilution of methylated DNA over successive cell divisions, and which is accompanied by active DNA-demethylation by the TET enzymes (which are now used as a measure of DNA-demethylation). Authors demonstrated that maternal ascorbate is required for proper DNA demethylation and the development of female germ cells. Maternal ascorbate deficiency did not affect overall embryonic development, whereas it results in decreased numbers of germ cells, delayed meiosis, and reduced fertility in adult offspring.
Vitamin C (ascorbate) deficiency therefore leads to an aberrant DNA-methylation profile — that includes incomplete demethylation of key regulators of meiosis and transposable elements. These data reveal that vitamin C deficiency during pregnancy partially imitates the loss of TET1 activity, and provide a potential intergenerational mechanism for the pregnant mother to adjust her level of fertility to environmental conditions.
DwN
· Nature 12 Sept 2019; 573: 271-275