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Kidney Week

Abstract: TH-OR020

Enhancer and Super-Enhancer Dynamics in Repair After Ischemic AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Wilflingseder, Julia, Brigham and Women’s Hospital / Harvard Medical School, Boston, Massachusetts, United States
  • Willi, Michaela, National Institute of Diabetes, Digestive and Kidney Diseases / NIH, Bethesda, Maryland, United States
  • Lee, Hye kyung, National Institute of Diabetes, Digestive and Kidney Diseases / NIH, Bethesda, Maryland, United States
  • Olauson, Hannes, Karolinska Institutet, Stockholm, Sweden
  • Ichimura, Takaharu, Brigham and Women’s Hospital / Harvard Medical School, Boston, Massachusetts, United States
  • Erben, Reinhold, University of Veterinary Medicine Vienna, Vienna, Austria
  • Valerius, M. Todd, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Hennighausen, Lothar, National Institute of Diabetes, Digestive and Kidney Diseases / NIH, Bethesda, Maryland, United States
  • Bonventre, Joseph V., Brigham and 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, H3K4me3, BRD4, Pol II) were performed on samples from repairing kidney cortex 2 days after ischemia/reperfusion injury (IRI) to identify activated genes, transcription factors, enhancer and super-enhancers associated with kidney repair. Further we investigated the role of super-enhancer activation in kidney repair through pharmacological BET inhibition using the small molecule JQ1 in acute kidney injury models in vivo.

Results

Response to kidney injury leads to genome-wide alteration 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 can be annotated to 62% and 63% of down- and up-regulated transcripts, respectively. The top 3 transcription factor binding motifs enriched in lost enhancer sites are Hnf4a, Esrrb and PPARE and in gained enhancer sites Fra1, Fosl2 and Atf3. ChIP-seq profiles of selected transcription factors show specific binding at corresponding enhancer sites. Super-enhancer analysis revealed 164 lost and 216 gained super-enhancer sites at IRI day 2. 385 super-enhancers maintain activity during repair. Pharmacological inhibition of enhancer activity by BRD4 inhibition before IRI leads 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

This is the first demonstration of BRD4 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 currently being tested in clinical trials in cancer patients who are at risk for AKI. Our analyses of enhancer dynamics after kidney injury in vivo have the potential to identify new targets for therapeutic intervention.

Funding

  • NIDDK Support