A low-complexity domain of Tet3 dioxygenase shields the oocyte methylome from oxidative erosion [RNA-seq]

Dynamic DNA methylation and demethylation regulate gene expression during development. While DNA methyltransferases (DNMTs) establish and maintain cytosine methylation patterns, Ten-eleven translocation (Tet) dioxygenases catalyze sequential oxidation of 5-methylcytosine (5mC) to promote demethylation. Target-specific 5mC oxidation requires precise regulation of the Tet enzymatic activity. However, the mechanism underlying their activity control remains largely unexplored. Here we show a large low-complexity domain (LCD), present within the catalytic domain of Tet3, functions to repress the dioxygenase activity. Recombinant LCD-deleted Tet3 exhibits enhanced activity to convert 5mC into oxidized species. Deletion of the Tet3 LCD in mouse oocytes renders 5mC oxidation indiscriminately across the genome, leading to most prominently the derepression of ERVK retrotransposons and upregulation of adjacent genes. The extensive 5mC oxidation is associated with impairments in oocyte development. These findings suggest an intrinsic auto-regulatory mechanism of Tet3 dioxygenase operating to ensure a tight regulation of its enzymatic activity to achieve spatiotemporal specificity of methylome reprogramming during oocyte development. Expression profiling by high throughput sequencing in WT, Tet3 LCD KO, Dnmt3a KO, Dnmt3a, Tet3 LCD DKO, Tet3 LCD KO HD Mut, Tet3 KO and Tet1,2,3 TKO GV oocytes.