Enhancer and super-enhancer dynamics in repair after ischemic acute kidney injury

Julia Wilflingseder (), Michaela Willi, Hye Kyung Lee, Hannes Olauson, Jakub Jankowski, Takaharu Ichimura, Reinhold Erben, M. Todd Valerius, Lothar Hennighausen and Joseph V. Bonventre ()
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Julia Wilflingseder: Harvard Medical School
Michaela Willi: NIDDK, NIH
Hye Kyung Lee: NIDDK, NIH
Hannes Olauson: Harvard Medical School
Jakub Jankowski: NIDDK, NIH
Takaharu Ichimura: Harvard Medical School
Reinhold Erben: University of Veterinary Medicine
M. Todd Valerius: Harvard Medical School
Lothar Hennighausen: NIDDK, NIH
Joseph V. Bonventre: Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract The endogenous repair process can result in recovery after acute kidney injury (AKI) with adaptive proliferation of tubular epithelial cells, but repair can also lead to fibrosis and progressive kidney disease. There is currently limited knowledge about transcriptional regulators regulating these repair programs. Herein we establish the enhancer and super-enhancer landscape after AKI by ChIP-seq in uninjured and repairing kidneys on day two after ischemia reperfusion injury (IRI). We identify key transcription factors including HNF4A, GR, STAT3 and STAT5, which show specific binding at enhancer and super-enhancer sites, revealing enhancer dynamics and transcriptional changes during kidney repair. Loss of bromodomain-containing protein 4 function before IRI leads to impaired recovery after AKI and increased mortality. Our comprehensive analysis of epigenetic changes after kidney injury in vivo has the potential to identify targets for therapeutic intervention. Importantly, our data also call attention to potential caveats involved in use of BET inhibitors in patients at risk for AKI.

Date: 2020
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DOI: 10.1038/s41467-020-17205-5

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