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Abstract: FR-PO388

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

Session Information

Category: Development‚ Stem Cells‚ and Regenerative Medicine

  • 500 Development‚ Stem Cells‚ and Regenerative Medicine

Authors

  • Liang, Xiujie, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Aranyi, Tamas, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Zhou, Jianfu, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Guan, Yuting, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Hu, Hailong, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Liu, Hongbo, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Group or Team Name

  • Susztak lab
Background

Nephron endowment is a key determinant of later life hypertension and kidney disease. Epigenetic changes are key regulators of gene expression. Here we studied whether epigenetic changes, specifically the ten–eleven translocation (Tet) DNA demethylase family, Tet1, Tet2, and Tet3-mediated active DNA hydroxymethylation is necessary for gene expression regulation and kidney differentiation.

Methods

We generated mice with deletion of Tet1, Tet2 or Tet3 in Six2 positive nephron progenitors (NP) and performed unbiased omics profiling, whole genome bisulfite sequencing on isolated Six positive NP and single cell RNA sequencing on newborn kidneys.

Results

We did not observe changes in development or kidney function in mice with nephron progenitor-specific deletion of Tet1, Tet2, Tet3 or Tet1/Tet2 or Tet1/Tet3. On the other hand, mice with combined Tet2 and Tet3 loss in Six2-positive NPCs failed to form nephrons leading to kidney failure and perinatal death. Tet2 and Tet3 loss in Six2-positive NPs resulted in defect in mesenchymal to epithelial transition and renal vesicle differentiation. Whole genome bisulfite sequencing, single cell RNA sequencing, and gene and protein expression assay identified a defect in expression in genes in the WNT-β-catenin signaling pathway in absence of Tet2 and Tet3 due to a failure in demethylation of these loci.

Conclusion

Our results indicate the key role of Tet2 and Tet3-mediated active cytosine hydroxymethylation in NPs in kidney development and nephron endowment.

Graph abstract

Funding

  • NIDDK Support