title: Genome-wide methylation profiling of ADPKD identified epigenetically regulated genes associated with renal cyst development.
abstract: 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.
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, 140-742, Korea, milkmi@sookmyung.ac.kr.
authors.forename: Yu Mi
authors.initials: YM
authors.lastname: Woo
authors.forename: Jae-Bum
authors.initials: JB
authors.lastname: Bae
authors.forename: Yeon-Hee
authors.initials: YH
authors.lastname: Oh
authors.forename: Young-Gun
authors.initials: YG
authors.lastname: Lee
authors.forename: Min Joo
authors.initials: MJ
authors.lastname: Lee
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Park
authors.forename: Jung-Kyoon
authors.initials: JK
authors.lastname: Choi
authors.forename: Sunyoung
authors.initials: S
authors.lastname: Lee
authors.forename: Yubin
authors.initials: Y
authors.lastname: Shin
authors.forename: Jaemyun
authors.initials: J
authors.lastname: Lyu
authors.forename: Hye-Yoon
authors.initials: HY
authors.lastname: Jung
authors.forename: Yeon-Su
authors.initials: YS
authors.lastname: Lee
authors.forename: Young-Hwan
authors.initials: YH
authors.lastname: Hwang
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Kim
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Park
mesh_terms: D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D055028:Comparative Genomic Hybridization; D019295:Computational Biology; D003560:Cysts / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D004285:Dogs; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D020868:Gene Silencing; D055106:Genome-Wide Association Study; D006801:Humans; D007668:Kidney / Q000473:pathology*; D061985:Madin Darby Canine Kidney Cells; D009154:Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000473:pathology; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D012313:RNA; D050396:TRPP Cation Channels; D014157:Transcription Factors