Demethylation in Early Embryonic Development and Memory

Abstract

DNA repair processes arose early in evolution. During evolution, DNA base excision repair apparently acquired additional roles in demethylation of cytosines in DNA. Demethylation is central to two mammalian fundamental processes. Embryonic reprogramming and neuronal memory require rapid gene expression alterations depending in part on demethylations. The active demethylation reactions in both processes primarily depend, first, on the family of 5-methylcytosine oxidases sharing the acronym ten-eleven translocation (TET methylcytosine dioxygenases) and, second, on DNA base excision repair enzymes. In mice, within 6 h of fertilization, the paternal chromosomes are close to 100% actively demethylated through TET and repair activity. (Methylation of maternal DNA is blocked during subsequent cycles of replication, so methyl groups on maternal DNA, passively, becomes highly diluted over the next 4 days.) Rats subjected to one instance of contextual fear conditioning create an especially strong long-term memory. At 24 h after training, 9.2% of the genes in the rat genomes of hippocampus neurons are differentially methylated, including over 500 genes with demethylation. The emergence of embryonic development in evolution depended on preexisting DNA methylation/demethylation pathways to modify gene expression. The further emergence of memory likely evolved from the earlier set of methylation/demethylation capabilities associated with embryonic development.

Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring

“…Folate is a water-soluble vitamin obtained from the diet that is essential for vertebrates. It is incorporated as an essential cofactor for the synthesis of nucleotides and the generation of S-adenosylmethionine (SAM) which serves as a universal donor of methyl groups for DNA, RNA and proteins implicated in gene regulation during early development [1][2][3][4] . Maternal folate deficiency leads to severe neural tube defects and craniofacial anomalies of descendants [5][6][7] .…”