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.
| Original language | English |
|---|---|
| Pages (from-to) | 281-297 |
| Number of pages | 17 |
| Journal | Human Genetics |
| Volume | 133 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2014 Mar 1 |
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All Science Journal Classification (ASJC) codes
- Genetics
- Genetics(clinical)
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Genome-wide methylation profiling of ADPKD identified epigenetically regulated genes associated with renal cyst development. / 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.
In: Human Genetics, Vol. 133, No. 3, 01.03.2014, p. 281-297.Research output: Contribution to journal › Article
TY - JOUR
T1 - Genome-wide methylation profiling of ADPKD identified epigenetically regulated genes associated with renal cyst development
AU - Woo, Yu Mi
AU - Bae, Jae Bum
AU - Oh, Yeon Hee
AU - Lee, Young Gun
AU - Lee, Min Joo
AU - Park, Eun Young
AU - Choi, Jung Kyoon
AU - Lee, Sunyoung
AU - Shin, Yubin
AU - Lyu, Jaemyun
AU - Jung, Hye Yoon
AU - Lee, Yeon Su
AU - Hwang, Young Hwan
AU - Kim, Young-Joon
AU - Park, Jong Hoon
PY - 2014/3/1
Y1 - 2014/3/1
N2 - 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.
AB - 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.
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U2 - 10.1007/s00439-013-1378-0
DO - 10.1007/s00439-013-1378-0
M3 - Article
VL - 133
SP - 281
EP - 297
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 3
ER -