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Kidney Week

Abstract: TH-PO127

Enhancer and Super-Enhancer Dynamics in Kidney Repair

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Wilflingseder, Julia, Brigham & Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
  • Willi, Michaela, National Institute of Health, Bethesda, Maryland, United States
  • Ichimura, Takaharu, Brigham & Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
  • Wang, Chaochen, National Institute of Health, Bethesda, Maryland, United States
  • Olauson, Hannes, Karolinska Institute, Stockholm, Sweden
  • Valerius, M. Todd, Brigham & Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
  • Erben, Reinhold, University of Veterinary Medicine, Vienna, Austria
  • Hennighausen, Lothar, National Institute of Health, Bethesda, Maryland, United States
  • Bonventre, Joseph V., Brigham & Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
Background

The endogenous repair process of the mammalian kidney allows rapid recovery after acute kidney injury (AKI) through robust proliferation of tubular epithelial cells. There is currently limited understanding of which transcriptional regulators activate these repair programs. Here we investigate the existence of enhancer dynamics in the regenerating mouse kidney.

Methods

RNA-seq and ChIP-seq (H3K27ac, H3K4m3, BRD4, MED1, POL2) were performed on samples from repairing kidney cortex 4 hours and 2 days after ischemia/reperfusion injury (IRI) to identify activated genes, transcription factors, enhancer and super-enhancer dynamics. Further, we investigated the role of super-enhancer activation after IRI through pharmacological BET inhibition via the small chemical compound JQ1 in vitro and in AKI models in vivo.

Results

AKI leads to genome-wide alterations in enhancer repertoire in vivo. We identified 16,781 enhancer sites (H3K27ac / BRD4 positive, H3K4me3 negative) active in Sham and IRI samples; 6,512 lost and 9,774 gained after IRI. The lost and gained enhancer sites could be annotated to 62% and 63% of down- and up-regulated transcripts after AKI, respectively. The top 5 transcription factor binding motifs enriched in lost enhancer sites are Hnf4a, Esrrb, PPARE, RXR and Esrra. In contrast Fra1, Fosl2, Atf3, Jun-AP1 and BATF binding motifs are enriched in gained enhancer sites after injury. Both transcription factor groups show corresponding mRNA changes after injury. Super-enhancer analysis reveals 164 lost and 216 gained super-enhancer sites after IRI. 385 super-enhancers maintain activity before and after injury. Pharmacological inhibition of super-enhancer activity by BRD4 inhibition (JQ1 50 mg/kg/day) before IRI led to suppression of 40% of injury-induced transcripts associated with cell cycle regulation, and significantly increased mortality between days 2 and 3 after AKI.

Conclusion

These results are the first demonstration of enhancer and super-enhancer function in the repairing kidney. In addition, our data call attention to potential caveats for use of small molecule inhibitors of BET proteins that are already being tested in clinical trials. Our comprehensive analysis of enhancer changes after kidney injury in vivo has the potential to identify new targets for therapeutic intervention.

Funding

  • NIDDK Support