Enhancer and super-enhancer landscape in polycystic kidney disease

Widespread aberrant gene expression is a pathological hallmark of polycystic kidney disease (PKD). Numerous pathogenic signaling cascades, including c-Myc, Fos, and Jun, are transactivated. However, the underlying epigenetic regulators are poorly defined. Here we show that H3K27ac, an acetylated modification of DNA packing protein histone H3 that marks active enhancers, is elevated in mouse and human samples of autosomal dominant PKD. Using comparative H3K27ac ChIP-Seq analysis, we mapped over 16000 active intronic and intergenic enhancer elements in Pkd1-mutant mouse kidneys. We found that the cystic kidney epigenetic landscape resembles that of a developing kidney, and over 90% of upregulated genes in Pkd1-mutant kidneys are co-housed with activated enhancers in the same topologically associated domains. Furthermore, we identified an evolutionarily conserved enhancer cluster downstream of the c-Myc gene and super enhancers flanking both Jun and Fos loci in mouse and human models of autosomal dominant PKD. Deleting these regulatory elements reduced c-Myc, Jun, or Fos abundance and suppressed proliferation and 3D cyst growth of Pkd1- mutant cells. Finally, inhibiting glycolysis and glutaminolysis or activating Ppara in Pkd1-mutant cells lowerd global H3K27ac levels and its abundance on c-Myc enhancers. Thus, our work suggests that epigenetic rewiring mediates the transcriptomic dysregulation in PKD, and the regulatory elements can be targeted to slow cyst growth.Kidney International (2023) 103, 87-99; https://doi.org/10.1016/ j.kint.2022.08.039 Copyright (c) 2022, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Automated summary

This study found elevated levels of H3K27ac, an acetylated modification of the DNA packing protein histone H3 that marks active enhancers, in polycystic kidney disease (PKD). Through comparative analysis, the researchers mapped over 16000 active intronic and intergenic enhancer elements in the kidneys of Pkd1-mutant mice. They also identified enhancer clusters that coexist with activated genes in PKD models, and deleting these regulatory elements suppressed cell proliferation and cyst growth. Furthermore, inhibiting glycolysis and glutaminolysis or activating Ppara reduced global H3K27ac levels and abundance on c-Myc enhancers. Therefore, epigenetic rewiring may play a role in the dysregulation of gene expression in PKD, and targeting the regulatory elements could potentially slow cyst growth.