Super-enhancer-driven metabolic reprogramming promotes cystogenesis in autosomal dominant polycystic kidney disease
Super-enhancer-driven metabolic reprogramming promotes cystogenesis in autosomal dominant polycystic kidney disease
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超级增强子驱动的代谢重编程促进常染色体显性多囊肾病的囊肿发生
DOI：
10.1038/s42255-020-0227-4
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发表时间：
2020
影响因子：
20.8
通讯作者：
Yupeng Chen
中科院分区：
文献类型：
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作者：
Zeyun Mi;Y;ong Song;Xinyi Cao;Yi Lu;Zhiheng Liu;Xu Zhu;Meijuan Geng;Yongzhan Sun;Bingxue Lan;Chaoran He;Hui Xiong;Lirong Zhang;Yupeng Chen
代谢重编程是常染色体显性多囊肾病（ADPKD）进展的关键病理因素，但囊性细胞代谢失调的分子机制尚不清楚。超级增强子（se）是一大群转录增强子，它们驱动细胞身份和疾病基因的强劲表达。在这里，我们发现se在囊细胞形成过程中经历了广泛的重塑，并且se相关转录本在囊细胞的代谢过程中最为丰富。周期蛋白依赖性激酶7 （CDK7）是一种组装和维持se所需的转录激酶，或AMP脱氨酶3 （AMPD3）是se驱动和CDK7控制的代谢靶基因之一，抑制周期蛋白依赖性激酶7 （CDK7）会延迟ADPKD小鼠模型中的囊肿生长。在一组ADPKD患者中，CDK7表达频繁升高，其表达与AMPD3表达和疾病严重程度相关。总之，我们的研究结果阐明了SE在膀胱发生过程中控制代谢基因转录的机制，并确定了SE驱动的代谢重编程是ADPKD治疗的一个有希望的治疗靶点。
Metabolic reprogramming is emerging as a key pathological contributor to the progression of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying dysregulated cellular metabolism in cystic cells remain elusive. Super-enhancers (SEs) are large clusters of transcriptional enhancers that drive robust expression of cell identity and disease genes. Here, we show that SEs undergo extensive remodelling during cystogenesis and that SE-associated transcripts are most enriched for metabolic processes in cystic cells. Inhibition of cyclin-dependent kinase 7 (CDK7), a transcriptional kinase required for assembly and maintenance of SEs, or AMP deaminase 3 (AMPD3), one of the SE-driven and CDK7-controlled metabolic target genes, delays cyst growth in ADPKD mouse models. In a cohort of people with ADPKD, CDK7 expression was frequently elevated, and its expression was correlated with AMPD3 expression and disease severity. Together, our findings elucidate a mechanism by which SE controls transcription of metabolic genes during cystogenesis, and identify SE-driven metabolic reprogramming as a promising therapeutic target for ADPKD treatment.