Tet3 CXXC Domain and Dioxygenase Activity Cooperatively Regulate Key Genes for Xenopus Eye and Neural Development

Ten-Eleven Translocation (Tet) family of dioxygenases dynamically regulates DNA methylation and has been implicated in cell lineage differentiation and oncogenesis. Yet their functions and mechanisms of action in gene regulation and embryonic development are largely unknown. Here, we report that Xenopus Tet3 plays an essential role in early eye and neural development by directly regulating a set of key developmental genes. Tet3 is an active 5mC hydroxylase regulating the 5mC/5hmC status at target gene promoters. Biochemical and structural studies further demonstrate that the Tet3 CXXC domain is critical for specific Tet3 targeting. Finally, we show that the enzymatic activity and CXXC domain are both crucial for Tet3’s biological function. Together, these findings define Tet3 as a transcription regulator and reveal a molecular mechanism by which the 5mC hydroxylase and DNA binding activities of Tet3 cooperate to control target gene expression and embryonic development. [Display omitted] ► Tet3 regulates key genes essential for eye and neural development in Xenopus ► Tet3 regulates gene expression partly via modulating 5mC/5hmC status at the promoter ► Tet3 CXXC domain processes unique DNA binding properties critical for Tet3 targeting ► Both the CXXC domain and hydroxylase activity are required for Tet3 function Xenopus Tet3 CXXC domain exhibits a unique DNA binding mode and is critical for its targeting. The DNA binding and 5mC hydroxylase activities of Tet3 cooperate to control the expression of key genes in early eye and neural development.