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

Yu Mi Woo, Jae Bum Bae, Yeon Hee Oh, Young Gun Lee, Min Joo Lee, Eun Young Park, Jung Kyoon Choi, Sunyoung Lee, Yubin Shin, Jaemyun Lyu, Hye Yoon Jung, Yeon Su Lee, Young Hwan Hwang, Young Joon Kim, Jong Hoon Park

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)281-297
Number of pages17
JournalHuman Genetics
Issue number3
Publication statusPublished - 2014 Mar

Bibliographical note

Funding Information:
Acknowledgments This research was supported by grants from the Korean Ministry of Science and Technology to Y-J.K (Global Research Lab). This work was also supported by the Bio & Medical Technology Development Program of the NRF (2012M3A9D1054518 and 2010-0019867). The authors declare no competing financial interests. Human kidney tissues of RCC and ADPKD patients were obtained from Dr. Curie Ahn at Department of Nephrology in Seoul National University Hospital. Histology of human normal and ADPKD kidney tissues was analyzed by professor Duk-Hee Kang at Department of Nephrology in Ewha Woman’s University.

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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