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Kidney Week

Abstract: SA-PO814

Unraveling the Role of TET2 Gene Variants in Kidney Disease Development: A Multi-Omics Approach

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Liang, Xiujie, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Liu, Hongbo, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Zhou, Jianfu, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Abedini, Amin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Hu, Hailong, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Sanchez Navarro, Andrea, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Kloetzer, Konstantin A., University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Group or Team Name

  • Susztak Lab.
Background

In the quest to understand the genetic causes of kidney disease, Genome-wide association studies (GWAS) have recognized hundreds of sites, yet the precise genes, variants, and pathways remain ambiguous.

Methods

To pinpoint the genes linked to kidney disease, we combined kidney function GWAS, human kidney expression quantitative trait analysis (eQTL), and methylation quantitative trait analysis (meQTL). To discover the variants that modify gene expression in kidney cells, we utilized single-cell chromatin accessibility (snATACseq) and (Crispr-based) genome editing. We created kidney-specific Tet2 knockout mice and manipulated gene expression in human kidney cells using CRISPR to study its role in kidney disease progression. We performed single-nucleus multiomics studies in knock-out mice to delve into the role of Tet2.

Results

We identified the ten–eleven translocation (Tet) DNA demethylase TET2, and the variants that change its expression in kidney tubule cells as a novel kidney disease risk gene, risk loci and target cell type. Experiments with kidney-specific Tet2 knockout mouse models confirmed its protective roles in cisplatin-induced acute kidney disease and UUO/adenine-induced chronic kidney disease and kidney fibrosis development. Single-nucleus profiling of Tet2 knock-out mice indicated changed expression in genes related to cellular differentiation in the absence of Tet2. Further cellular studies suggested that Tet2 might be vital for tubule cell differentiation and could instigate kidney disease development by altering the cytosine hydroxymethylation level of associated differentiation genes.

Conclusion

Our findings underscore the crucial role of Tet2-mediated active cytosine hydroxymethylation on genes associated with differentiation in tubule cells in the onset of kidney disease.

Funding

  • NIDDK Support