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Abstract: SU-OR08

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, Renal Division, Harvard Medical School, Boston, Massachusetts, United States
  • Willi, Michaela, Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, United States
  • Lee, Hye kyung, Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, United States
  • Olauson, Hannes, Division of Renal Medicine, Department of Clinical Sciences, Intervention and Technology, Stockholm, Sweden
  • Jankowski, Jakub, University of Veterinary Medicine, Department of Physiology, Pathophysiology and Endocrinology, Vienna, Austria
  • Ichimura, Takaharu, Brigham and Women’s Hospital, Renal Division, Harvard Medical School, Boston, Massachusetts, United States
  • Erben, Reinhold, University of Veterinary Medicine, Department of Physiology, Pathophysiology and Endocrinology, Vienna, Austria
  • Valerius, M. Todd, Brigham and Women’s Hospital, Renal Division, Harvard Medical School, Boston, Massachusetts, United States
  • Hennighausen, Lothar, Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, United States
  • Bonventre, Joseph V., Brigham and Women’s Hospital, Renal Division, 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 and transcription factor dynamics in the regenerating mouse kidney.

Methods

RNA-seq and ChIP-seq (H3K27ac, H3K4m3, BRD4, BRD2, BRD3, Pol II, HNF4A, GR, STAT3 and STAT5) 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. Furthermore we investigated the role of enhancer dynamics in kidney repair through pharmacological BET inhibition using the small molecule JQ1 in AKI models in vivo.

Results

Response to injury leads to genome-wide alteration in enhancer repertoire in-vivo. We identified 16,781 enhancer and 380 super-enhancer sites (H3K27ac and BRD4 positive) with dynamic binding in SHAM and IRI samples; 6,512 enhancer, 164 super-enhancer lost and 9,774 enhancer, 214 super-enhancer gained after IRI. The lost and gained enhancer sites can be annotated to 62% and 63% of down- and up-regulated transcripts after AKI, respectively. ChIP-seq profiles of predicted transcription factors show specific binding at corresponding enhancer sites with dynamic binding of HNF4A, GR and STAT3. HNF4A and GR show a reduced binding at enhancer and super-enhancer sites after injury, whereas STAT3 binding can be observed at injury gained enhancer and super-enhancer sites. BET (BRD4) inhibition before IRI leads to suppression of 40% of injury-induced transcripts associated with cell cycle regulation, genome-wide Pol II pausing and significantly increased mortality after AKI.

Conclusion

This is the first demonstration of enhancer and super-enhancer and transcription factor binding dynamics in the repairing kidney. In addition, our data call attention to potential caveats for use of BET inhibitors that are currently being tested in clinical trials. Understanding of enhancer dynamics after kidney injury in vivo has the potential to lead to indentification of new targets for therapeutic intervention.

Funding

  • NIDDK Support