Enhancer and super-enhancer dynamics in repair after ischemic acute kidney injury.
Julia WilflingsederMichaela WilliHye Kyung LeeHannes OlausonJakub JankowskiTakaharu IchimuraReinhold G ErbenM Todd ValeriusLothar HennighausenJoseph V BonventrePublished in: Nature communications (2020)
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.
Keyphrases
- acute kidney injury
- transcription factor
- binding protein
- cardiac surgery
- dna binding
- ischemia reperfusion injury
- end stage renal disease
- gene expression
- healthcare
- chronic kidney disease
- multiple sclerosis
- cell proliferation
- public health
- machine learning
- risk factors
- oxidative stress
- signaling pathway
- newly diagnosed
- type diabetes
- small molecule
- working memory
- cardiovascular disease
- prognostic factors
- cardiovascular events
- genome wide identification
- nuclear factor
- high throughput
- deep learning
- circulating tumor cells
- cerebral ischemia
- blood brain barrier