Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development

Yi-An Ko,Katalin Susztak,Melissa Fazzari,James M Pullman,Ae Park,Davoud Mohtat,John M Greally,Maria Izquierdo,Masako Suzuki,Thomas Hostetter,Amit Verma,Hyun Kang,Deyou Zheng,Sang Han,Han Si

doi:10.1186/gb-2013-14-10-r108

Abstract

BackgroundOne in eleven people is affected by chronic kidney disease, a condition characterized by kidney fibrosis and progressive loss of kidney function. Epidemiological studies indicate that adverse intrauterine and postnatal environments have a long-lasting role in chronic kidney disease development. Epigenetic information represents a plausible carrier for mediating this programming effect. Here we demonstrate that genome-wide cytosine methylation patterns of healthy and chronic kidney disease tubule samples obtained from patients show significant differences.ResultsWe identify differentially methylated regions and validate these in a large replication dataset. The differentially methylated regions are rarely observed on promoters, but mostly overlap with putative enhancer regions, and they are enriched in consensus binding sequences for important renal transcription factors. This indicates their importance in gene expression regulation. A core set of genes that are known to be related to kidney fibrosis, including genes encoding collagens, show cytosine methylation changes correlating with downstream transcript levels.ConclusionsOur report raises the possibility that epigenetic dysregulation plays a role in chronic kidney disease development via influencing core pro-fibrotic pathways and can aid the development of novel biomarkers and future therapeutics.

Highlights

Clinical retrospective data indicate that altered nutrient availability during development could have a long lasting effect on the development of adult diseases, a phenomenon called 'programming'
P-value
We found that CKDspecific DMRs localized mostly to repressed chromatin regions, while transcription and enhancer regions showed the second highest enrichment

Summary

Introduction

Clinical retrospective data indicate that altered nutrient availability during development could have a long lasting effect on the development of adult diseases, a phenomenon called 'programming'. Hypertension and chronic kidney disease (CKD) show one of the highest sensitivities to intrauterine programming [1]. Epigenetic changes caused by altered intrauterine nutrient availability have been proposed as the mechanistic link for hypertension and CKD development [2]. Epidemiological studies indicate that adverse intrauterine and postnatal environments have a long-lasting role in chronic kidney disease development. We demonstrate that genome-wide cytosine methylation patterns of healthy and chronic kidney disease tubule samples obtained from patients show significant differences. To understand whether or not epigenetic changes occur and thereby potentially contribute to CKD development in patients, we performed genome-wide cytosine methylation profiling of tubule epithelial cells obtained from CKD and control kidneys. Examining the CKD epigenome can be an important first step in understanding the role of epigenetics outside the cancer field [12]

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Conclusion