Tet2- and Tet3-Mediated Cytosine Hydroxymethylation in Six2 Progenitor Cells in Mice Is Critical for Nephron Progenitor Differentiation and Nephron Endowment

Epigenetic changes have been proposed to mediate nephron endowment during development, a critical determinant of future renal disease development. Hydroxymethyl cytosine, an epigenetic modification important for gene regulation, is abundant in the human kidney, but its physiologic role and the role of DNA demethylase enzymes encoded by the Tet1, Tet2, or Tet3, which mediate cytosine hydroxymethylation, are unclear. By genetically deleting Tet1, Tet2, or Tet3 in nephron progenitors in mice, the authors showed that combined Tet2 and Tet3 loss in nephron progenitors cause defective kidney development, leading to kidney failure and perinatal death. Tet2 and Tet3 deletion also caused an alteration in demethylation and expression of genes critical for nephron formation. These findings establish that Tet2- and Tet3-mediated cytosine hydroxymethylation in nephron progenitors plays a critical role in nephron endowment.