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

Yi-An Ko1, Davoud Mohtat1, Masako Suzuki2, Ae Seo Deok Park1, Maria Concepcion Izquierdo1, Sang Youb Han1, Hyun Mi Kang1, Han Si1, Thomas Hostetter6, James M Pullman3, Melissa Fazzari24, Amit Verma5, Deyou Zheng2, John M Greally2* and Katalin Susztak1*

Author Affiliations

1 Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania United States,, 415 Curie Blvd, Philadelphia, PA 19104, USA

2 Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA

3 Department of Pathology, Montefiore Medical Center, Bronx, NY 10461, USA

4 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA

5 Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA

6 Case Western Reserve University, Cleveland, Ohio 44106, USA

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Genome Biology 2013, 14:R108  doi:10.1186/gb-2013-14-10-r108

Published: 7 October 2013

Abstract

Background

One 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.

Results

We 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.

Conclusions

Our 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.