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Kidney Week

Abstract: SA-PO333

Profiling the Epigenetic Landscape of the African Spiny Mouse, A Mammalian Model of Kidney Regeneration

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Nguyen, Elizabeth D., University of Washington School of Medicine, Seattle, Washington, United States
  • Gere, Joshua, Seattle Children's Research Institute, Seattle, Washington, United States
  • Bae, Yeji, Seattle Children's Research Institute, Seattle, Washington, United States
  • Okamura, Daryl M., University of Washington School of Medicine, Seattle, Washington, United States
  • Collins, Sarah J., Seattle Children's Research Institute, Seattle, Washington, United States
  • Houghtaling, Scott Robert, Seattle Children's Research Institute, Seattle, Washington, United States
  • Miller, Danny, University of Washington School of Medicine, Seattle, Washington, United States
  • Suh, Kiheon, Seattle Children's Research Institute, Seattle, Washington, United States
  • Paquette, Alison G., University of Washington School of Medicine, Seattle, Washington, United States
  • Beier, David R., University of Washington School of Medicine, Seattle, Washington, United States
  • Majesky, Mark W., University of Washington School of Medicine, Seattle, Washington, United States
Background

The African spiny mouse is the first mammal to demonstrate full restoration of kidney function without fibrosis after injury (Okamura et al., 2021) and provides an opportunity to elucidate mechanisms promoting kidney regeneration. The transcriptome of the spiny mouse and house mouse kidneys are the same, but its response to injury is remarkably different, indicating that epigenetic control of gene expression may be the key to its regenerative capabilities. We hypothesize that the African spiny mouse kidney is poised to respond differently before injury occurs through accessible chromatin for critical genes that are regulated by histone methylation.

Methods

Single nuclei ATAC-sequencing identified accessible regions of chromatin in normal African spiny mouse kidneys (n=3). Cleavage Under Targets and Release Under Nuclease (CUT&RUN) identified which regulatory elements were targeted by activating (H3K4me3) and repressive (H3K27me3) histone marks in spiny mouse kidney (n=2). Data was aligned to a spiny mouse reference genome we constructed with long-read DNA sequencing. For data analysis, we used Cellranger for ATAC-seq clustering, SEACR for CUT&RUN peak calling and HOMER for peak annotation and motif detection.

Results

Single nuclei ATAC-seq data mapped to the spiny mouse reference genome at >85%. Over 4,300 high quality peaks were generated from 27,000 cells, generating 10 distinct clusters. CUT&RUN sequencing data mapped to the reference genome at >95%. 2608 consensus H3K4me3 peaks and 1560 consensus H3K27me3 peaks were detected. Several key progenitor motifs marked by H3K4me3 were significantly enriched in the spiny mouse kidney (p<0.01) and had accessible chromatin based on ATAC-seq data, including Nkx3.1, Osr1, Myb and Tead2.

Conclusion

This work demonstrates that chromatin for nephrogenic progenitor genes in spiny mouse is accessible and poised for transcription through histone methylation. These experiments are being extended to injured kidneys of the spiny mouse to identify how gene regulation is controlled by histone marks in the setting of kidney regeneration. These results will have an important positive impact by providing targets and potential mechanisms for the redirection of kidney injury towards regeneration of functional tissue.

Funding

  • NIDDK Support