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Enhancer and super-enhancer dynamics in repair after ischemic acute kidney injury.
Nature Communications ( IF 14.7 ) Pub Date : 2020-07-07 , DOI: 10.1038/s41467-020-17205-5
Julia Wilflingseder 1, 2, 3 , Michaela Willi 2 , Hye Kyung Lee 2 , Hannes Olauson 1, 4 , Jakub Jankowski 2, 3 , Takaharu Ichimura 1 , Reinhold Erben 3 , M Todd Valerius 1 , Lothar Hennighausen 2 , Joseph V Bonventre 1
Affiliation  

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.



中文翻译:


缺血性急性肾损伤后修复中的增强子和超级增强子动力学。



内源性修复过程可以导致急性肾损伤(AKI)后的恢复以及肾小管上皮细胞的适应性增殖,但修复也可能导致纤维化和进行性肾脏疾病。目前对调节这些修复程序的转录调节因子的了解有限。在此,我们通过 ChIP-seq 在缺血再灌注损伤 (IRI) 后第二天未受伤和修复的肾脏中建立了 AKI 后的增强子和超级增强子景观。我们鉴定了关键转录因子,包括 HNF4A、GR、STAT3 和 STAT5,它们在增强子和超级增强子位点表现出特异性结合,揭示了肾脏修复过程中的增强子动态和转录变化。 IRI 前含溴结构域蛋白 4 功能的丧失会导致 AKI 后的恢复受损并增加死亡率。我们对体内肾损伤后表观遗传变化的综合分析有可能确定治疗干预的目标。重要的是,我们的数据还提醒人们注意在有 AKI 风险的患者中使用 BET 抑制剂时可能需要注意的事项。

更新日期:2020-07-07
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