The simplest explanation: passive DNA demethylation in PGCs

Abstract

EMBO J (2013) 32 3, 340–353 doi:; DOI: 10.1038/emboj.2012.331; published online December 14 2012

Primordial germ cell (PGC) specification is one of two major developmental windows where modifications associated with global heterochromatin maintenance are erased. One of the most intriguing and confounding dynamics to rectify has been the apparent global depletion of cytosine methylation, which has been intensely scrutinized for nearly two decades. While numerous reports have suggested active catalytic removal as the primary mechanism, work by Saitou and colleagues presented in this issue of The EMBO Journal provide support for a simpler model whereby the downregulation of essential recruitment factors appears sufficient to erase this mark passively during a phase of rapid proliferation.

Figure 1

Proposed mechanisms for demethylation have suggested either complete catalytic removal of cytosine bases or passive dilution over replication in the absence of maintenance. Several replication-independent models have been posed. Activation Induced Cytidine Deaminase (AICDA) may deaminate methylated cytosines, with the resulting T/G mismatch targeted for Base Excision Repair (BER) through Thymidine DNA Glycosylase (TDG). Alternatively, hydroxymethylation (hme) as mediated by the TET enzymes, plus deamination via AICDA, may result in an atypical hydroxymethyluracyl base, which may also be targeted by BER. It has also been suggested that progressive rounds of oxidation may result in carboxylation, which is energetically unstable enough to be removed by a hypothetical carboxylase. In contrast to high energy, multistep processes, cytosine methylation can be oxidized to hydroxymethylcytosine, which may not be heritable over division. This ‘pulse’ of catalytic activity followed by progressive dilution as cells divide would be similar to the dynamics observed for global H3K9 dimethylation, which may involve histone demethylases (KDMs). Finally, the data presented by Kagiwada and colleagues suggest that division alone may be sufficient for demethylation in the absence of maintenance. In either division dependent model, with or without hydroxymethylation, downregulation of UHRF1 would ensure inefficient recruitment of DNMT1 to DNA during replication. Regulation of global heterochromatin through abrogated recruitment would again be similar to the regulation H3K9 dimethylation, where G9a is prohibited from targeting histones through repression of its cofactor GLP.