DNA methylation, which often occurs at the 5-carbon position of cytosine (5mC) located in CpG dinucleotide, is a key epigenetic hallmark and serves as a major epigenetic mechanism for establishing X-inactivation, parental imprinting and silencing retrotransposable elements during early embryogenesis in mammals. Accumulative evidence also suggests that DNA methylation plays key roles in transcriptional regulation 1. Observations of active global loss of 5mC during early development and local loss of 5mC concurrent with gene activation have led to the search for enzymes capable of active DNA demethylation of 5mC 2.

Of the 11 members of the CXXC domain-containing gene family identified in the human genome by bioinformatics, 4 have been characterized as chromatin modifiers (Supplementary information, Table S1). We asked whether any of the remaining seven members (1) share homology with reported oxidoreductive enzymes; (2) contain a potential oxidative catalytic domain; or (3) contain cofactor (i.e. NAD(P)+, FAD, iron, α-ketoglutarate)-binding motifs.

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