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Tet proteins are emerging as major epigenetic modulators of cell fate and plasticity. However, little is known about how Tet proteins are targeted to selected genomic loci in distinct biological contexts. Previously, a CXXC-type zinc finger domain in Tet1 was shown to bind CpG-rich DNA sequences. Interestingly, in human and mouse the  Tet2  and  Tet3  genes are adjacent to  Cxxc4  and  Cxxc10-1 , respectively. The CXXC domains encoded by these loci, together with those in  Tet1  and  Cxxc5 , identify a distinct homology group within the CXXC domain family. Here we provide evidence for alternative mouse Tet3 transcripts including the Cxxc10-1 sequence (Tet3 CXXC ) and for an interaction between Tet3 and Cxxc4.  In vitro  Cxxc4 and the isolated CXXC domains of Tet1 and Tet3 CXXC  bind DNA substrates with similar preference towards the modification state of cytosine at a single CpG site.  In vivo  Tet1 and Tet3 isoforms with and without CXXC domain hydroxylate genomic 5-methylcytosine with similar activity. Relative transcript levels suggest that distinct ratios of Tet3 CXXC  isoforms and Tet3-Cxxc4 complex may be present in adult tissues. Our data suggest that variable association with CXXC modules may contribute to context specific functions of Tet proteins.

Intrinsic and Extrinsic Connections of Tet3 Dioxygenase with CXXC Zinc Finger Modules