UniProt release 2011_10
Published October 19, 2011
The sound of silence
Cytosine methylation is the major and best characterized epigenetic modification of metazoan DNA. It is implicated in long-term gene silencing, X chromosome inactivation, genomic imprinting, etc. 5-methylcytosine (5mC) is recognized by methyl-binding proteins (MBDs), that in turn recruit repressive histone modifiers, such as H3K9 methyltransferases, to establish a heterochromatin state.
Cytosine base methylation is catalyzed by the C5-methyltransferase enzyme family. DNMT3A and DNMT3B methylate DNA de novo. DNMT1 maintains the methylation status across cell divisions. In the absence of DNMT1 activity, DNA methylation is progressively lost since methylation is not replicated onto the newly synthesized strand, leading to passive DNA demethylation.
However, passive DNA demethylation cannot account for rapid demethylation that occurs in the paternal genome in the zygote within the first 4 hours following fertilization or that observed in primordial germ cells, both of which are independent of DNA replication. While demethylases have been identified in Arabidopsis thaliana, the mechanism of active demethylation in mammals remained elusive (reviews). 2011 has unveiled the central role played by TET family members. These enzymes have already been shown to to catalyze the conversion of 5mC into 5-hydroxymethylcytosine. 5hmC can be further processed, either by G/T mismatch-specific thymine DNA glycosylase (TDG) or by deamination enzymes, such as APOBEC1 and AICDA/AID, and eventually removed and replaced by unmodified cytosine by base excision repair mechanism.
Interestingly, TET1 has a role in transcriptional repression, independently of its enzymatic activity. It binds a significant proportion of Polycomb group target genes and associates and colocalizes with the SIN3A co-repressor complex.
These new exciting data pave the way for understanding transcriptional fine-tuning during embryonic development, as well as in adult organisms and will keep us busy updating UniProtKB for quite a while.