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

Julia Wilflingseder,Jakub Jankowski,Hye Kyung Lee,Hannes Olauson,M Todd Valerius,Takaharu Ichimura,Lothar Hennighausen,Joseph V Bonventre,Michaela Willi,Reinhold Erben

doi:10.1038/s41467-020-17205-5

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.

Highlights

The endogenous repair process can result in recovery after acute kidney injury (AKI) with adaptive proliferation of tubular epithelial cells, but repair can lead to fibrosis and progressive kidney disease
We identified 216 injuryassociated super-enhancers consisting of 565 single enhancers, 164 super-enhancers lost during injury consisting of 419 enhancers and 385 SHARED super-enhancers consisting of 1630 enhancers, which are present in the kidney at baseline and in ischemia reperfusion injury (IRI) day 2 samples
At the Junb locus we find additional STAT3 binding after IRI indicating Junb activation by STAT3 (Fig. 4b)

Summary

Introduction

The endogenous repair process can result in recovery after acute kidney injury (AKI) with adaptive proliferation of tubular epithelial cells, but repair can lead to fibrosis and progressive kidney disease. A decrease of renal function can be reversed through the endogenous repair processes of the kidney, AKI is associated with a substantially increased risk of developing fibrosis and chronic kidney disease (CKD), especially if there is severe or repeated injury resulting in ‘maladaptive’ repair processes[4,5]. Surviving tubular epithelial cells are the main cellular source of the repair process in the kidney with robust proliferation to replace the cells lost as a result of the injury[6]. Studies have implicated enhancers in health and disease[14,15] Such findings raise the possibility of existing enhancer elements that engage with transcription factors in response to tissue damage to regulate genetic programs for kidney repair

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Conclusion