Epigenetic reprogramming: is deamination key to active DNA demethylation?

Abstract

DNA demethylation processes are important for reproduction, being central in epigenetic reprogramming during embryonic and germ cell development. While the enzymes methylating DNA have been known for many years, identification of factors capable of mediating active DNA demethylation has been challenging. Recent findings suggest that cytidine deaminases may be key players in active DNA demethylation. One of the most investigated candidates is activation-induced cytidine deaminase (AID), best known for its role in generating secondary antibody diversity in B cells. We evaluate evidence for cytidine deaminases in DNA demethylation pathways in vertebrates and discuss possible models for their targeting and activity regulation. These findings are also considered along with alternative demethylation pathways involving hydroxymethylation.

Activation-induced cytidine deaminase and active cytidine demethylation

“…However, there is no consensus on whether AID leads to demethylation in vivo, and, if so, on the relevance of this phenomenon for normal physiology and pathology. The difficulties raised by this hypothesis and models reconciling the biochemistry of AID with its role in active DNA demethylation have already been discussed in several publications [12][13][14][15][16][17]. We provide here an updated overview of published findings related to the possible role of AID in genome-wide and gene-specific demethylation, and propose questions we believe need to be addressed.…”

AID/APOBEC deaminases and cancer

“…Aside from mutational activity, cytidine deaminases have also been shown to participate in epigenetics through active DNA demethylation [64]. Cytosines in DNA can occur either in an unmethylated or methylated (5-methylcytosine) form and are often enriched in promoter regions in a CpG dinucleotide context where methylation is associated with gene silencing [64].…”

“…Cytosines in DNA can occur either in an unmethylated or methylated (5-methylcytosine) form and are often enriched in promoter regions in a CpG dinucleotide context where methylation is associated with gene silencing [64]. Deamination of methylated cytidines generates thymidines, which are removed by the DNA repair machinery [64]. Insertion of a non-methylated dC would hence result in dC demethylation [64].…”

Age, the environment and our reproductive future: bonking baby boomers and the future of sex

“…Furthermore, both the male and female germ lines express unique DNA methylation patterns that have a profound effect on fertility and the normality of development (Hammoud et al 2009(Hammoud et al , 2011. Detailed discussion of these epigenetic modulators of embryonic development is beyond the scope of this review; however, the field has been extensively, and expertly, reviewed in this journal in the recent past (Teperek-Tkacz et al 2011, Jenkins & Carrell 2012.…”