Genome-wide methylation profiling of ADPKD identified epigenetically regulated genes associated with renal cyst development

• Published in: Human genetics 2014-03, Vol.133 (3), p.281-297
• Main Authors: Woo, Yu Mi, Bae, Jae-Bum, Oh, Yeon-Hee, Lee, Young-Gun, Lee, Min Joo, Park, Eun Young, Choi, Jung-Kyoon, Lee, Sunyoung, Shin, Yubin, Lyu, Jaemyun, Jung, Hye-Yoon, Lee, Yeon-Su, Hwang, Young-Hwan, Kim, Young-Joon, Park, Jong Hoon
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Biomedical and Life Sciences; Biomedicine; Cancer; Cell Line; Chromatin Immunoprecipitation; Comparative Genomic Hybridization; Computational Biology; Criminal investigation; Cysts; Cysts - genetics; Cysts - pathology; DNA Methylation; Dogs; Down-Regulation; Epigenesis, Genetic; Epigenetics; Gene Expression Profiling; Gene Function; Gene Silencing; Genes; Genetic aspects; Genome-Wide Association Study; Genomes; Genomics; Human Genetics; Humans; Kidney - pathology; Kidney diseases; Madin Darby Canine Kidney Cells; Metabolic Diseases; Methylation; Molecular Medicine; Mutation; Original Investigation; Pathogenesis; Polycystic Kidney, Autosomal Dominant - genetics; Polycystic Kidney, Autosomal Dominant - pathology; Protein binding; Proteins; RNA - genetics; RNA - isolation & purification; Sequence Analysis, DNA; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism; TRPP Cation Channels - genetics; TRPP Cation Channels - metabolism
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-013-1378-0

Autosomal dominant polycystic kidney disease (ADPKD) is a common human genetic disease characterized by the formation of multiple fluid-filled cysts in bilateral kidneys. Although mutations in polycystic kidney disease 1 ( PKD1 ) are predominantly responsible for ADPKD, the focal and sporadic property of individual cystogenesis suggests another molecular mechanism such as epigenetic alterations. To determine the epigenomic alterations in ADPKD and their functional relevance, ADPKD and non-ADPKD individuals were analyzed by unbiased methylation profiling genome-wide and compared with their expression data. Intriguingly, PKD1 and other genes related to ion transport and cell adhesion were hypermethylated in gene-body regions, and their expressions were downregulated in ADPKD, implicating epigenetic silencing as the key mechanism underlying cystogenesis. Especially, in patients with ADPKD, PKD1 was hypermethylated in gene-body region and it was associated with recruitment of methyl-CpG-binding domain 2 proteins. Moreover, treatment with DNA methylation inhibitors retarded cyst formation of Madin-Darby Canine Kidney cells, accompanied with the upregulation of Pkd1 expression. These results are consistent with previous studies that knock-down of PKD1 was sufficient for cystogenesis. Therefore, our results reveal a critical role for hypermethylation of PKD1 and cystogenesis-related regulatory genes in cyst development, suggesting epigenetic therapy as a potential treatment for ADPKD.