Abstract: SA-OR084

BET Protein Family Member BRD4 Promotes Transcription through Super-Enhancer Activation in Kidney Repair and Progression of Fibrosis

Session Information

Category: Acute Kidney Injury

  • 002 AKI: Repair and Regeneration

Authors

  • Wilflingseder, Julia, Brigham & Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
  • Willi, Michaela, NIDDK/NIH, Bethesda, Maryland, United States
  • Wang, Chaochen, NIDDK/NIH, Bethesda, Maryland, United States
  • Olauson, Hannes, Brigham & Women's Hospital/Harvard Medical School, Boston, United States
  • Ichimura, Takaharu, Brigham & Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
  • Valerius, M. Todd, Brigham & Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
  • Hennighausen, Lothar, NIDDK/NIH, Bethesda, Maryland, United States
  • Bonventre, Joseph V., Brigham & Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
Background

The mammalian kidney can repair after acute kidney injury (AKI) through robust proliferation of tubular epithelial cells. Maladaptive repair can however lead to kidney fibrosis and chronic kidney disease (CKD). There is currently limited understanding of which transcriptional regulators activate these repair programs and how transcriptional deregulation leads to CKD. Here we investigate the existence of enhancer regulatory elements occupied by BRD4 that are activated in regenerating mouse kidney.

Methods

RNA-Seq and CHIP-Seq (H3K27ac, H3K4m3, BRD4, MED1, POL2) were performed on samples from repairing kidney cortex day 2 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 via the small chemical compound JQ1 in vitro and in three kidney injury models in vivo.

Results

Here we establish the enhancer and super-enhancer landscape associated with kidney injury and repair. Furthermore, we identify key transcription factors, which cooperate with BRD4 and MED1 at enhancer sites, likely activating repair programs in tubular epithelial cells. Loss of BRD4 function by systemic administration of the BET inhibitor JQ1 (50mg/kg/d) before IRI leads to impaired recovery after AKI and increased mortality between day 2 and 3 after injury. By contrast, inhibition of prolonged transcriptional responses during repair, through blockade of BRD4 at enhancer sites via JQ1 starting at day 2 and day 7 after injury, ameliorates interstitial fibrosis in UUO, unilateral IRI and aristolochic acid (AA) kidney injury models at day 10 and day 21, respectively.

Conclusion

These results are the first demonstration of BRD4 enhancer and super-enhancer function in the repairing kidney, providing a critical link between AKI and CKD. 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 in patient at risk for AKI. Our comprehensive analysis of epigenetic changes after kidney injury in vivo has the potential to identify new targets for therapeutic intervention.

Funding

  • NIDDK Support