JoVE - Journal of Visualized Experiments
JoVE Visualize
Contact Us

Predicting proximal tubule failed repair drivers through regularized regression analysis of single cell multiomic sequencing

  • 0Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
Nature Communications +

|

February 12, 2024

|

February 12, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

Injured kidney cells can fail to repair, becoming proinflammatory and profibrotic, potentially leading to kidney disease. Researchers identified NFAT5 as a key driver of this failed repair state using multiomic sequencing and gene regulatory network analysis.

Area Of Science

  • Nephrology
  • Molecular Biology
  • Genomics

Background

  • Renal proximal tubule epithelial cells possess intrinsic repair capabilities after injury.
  • A subset of these cells can adopt a maladaptive, proinflammatory, and profibrotic phenotype, contributing to kidney fibrosis and chronic kidney disease.
  • This transition from healthy repair to failed repair involves distinct transcriptomic and epigenomic alterations.

Purpose Of The Study

  • To investigate the gene regulatory networks driving the transition from healthy to failed repair in proximal tubule cells.
  • To identify key regulatory elements and drivers of maladaptive cellular responses in kidney injury.
  • To leverage multiomic data for understanding the molecular mechanisms underlying kidney disease progression.

Main Methods

  • Development of a regularized regression approach for constructing genome-wide parametric gene regulatory networks.
  • Generation of a single nucleus multiomic dataset (joint RNA- and ATAC-sequencing) from adult human kidney samples.
  • Application of the developed method to analyze multiomic data and identify regulatory drivers of failed kidney repair.

Main Results

  • The developed method effectively predicts key cis- and trans-regulatory elements involved in the healthy to failed repair transition.
  • Analysis of the human kidney multiomic dataset revealed critical regulatory drivers of maladaptive cellular states.
  • NFAT5 was identified as a significant driver of the maladaptive proximal tubule cell phenotype following injury.

Conclusions

  • Single nucleus multiomic sequencing combined with advanced computational analysis provides powerful insights into kidney injury repair mechanisms.
  • The study successfully identified NFAT5 as a key regulator promoting a profibrotic and proinflammatory state in proximal tubule cells.
  • Understanding these regulatory networks offers potential therapeutic targets for preventing kidney fibrosis and chronic kidney disease.