Super-enhancer-driven metabolic reprogramming promotes cystogenesis in autosomal dominant polycystic kidney disease.

Nature Metabolism
Zeyun MiYupeng Chen

Abstract

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.

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Citations

Feb 8, 2021·The American Journal of Pathology·Jennifer Q J ZhangGopala K Rangan
May 21, 2021·Biochemical and Biophysical Research Communications·Xingquan ZhouXu Zhu
Jun 25, 2021·Journal of the American Society of Nephrology : JASN·Zhiheng LiuYupeng Chen

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BETA
immunoprecipitation
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PCR
ChIP
flow cytometry
deamination
Assay

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GraphPad Prism
MACS
SOAPnuke
ImageJ
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