DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

Chunyuan Guo, Lirong Pei, Xiao Xiao, QingQing Wei, Jiankang Chen, Hanfei Ding, Shuang Huang, Guoping Fan, Huidong Shi, Zheng Dong

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

DNA methylation is an epigenetic mechanism that regulates gene transcription without changing primary nucleotide sequences. In mammals, DNA methylation involves the covalent addition of a methyl group to the 5-carbon position of cytosine by DNA methyltransferases (DNMTs). The change of DNA methylation and its pathological role in acute kidney injury (AKI) remain largely unknown. Here, we analyzed genome-wide DNA methylation during cisplatin-induced AKI by reduced representation bisulfite sequencing. This technique identified 215 differentially methylated regions between the kidneys of control and cisplatin-treated animals. While most of the differentially methylated regions were in the intergenic, intronic, and coding DNA sequences, some were located in the promoter or promoter-regulatory regions of 15 protein-coding genes. To determine the pathological role of DNA methylation, we initially examined the effects of the DNA methylation inhibitor 5-aza-2'-deoxycytidine and showed it increased cisplatin-induced apoptosis in a rat kidney proximal tubular cell line. We further established a kidney proximal tubule-specific DNMT1 (PT-DNMT1) knockout mouse model, which showed more severe AKI during cisplatin treatment than wild-type mice. Finally, interferon regulatory factor 8 (Irf8), a pro-apoptotic factor, was identified as a hypomethylated gene in cisplatin-induced AKI, and this hypomethylation was associated with a marked induction of Irf8. In the rat kidney proximal tubular cells, the knockdown of Irf8 suppressed cisplatin-induced apoptosis, supporting a pro-death role of Irf8 in renal tubular cells. Thus, DNA methylation plays a protective role in cisplatin-induced AKI by regulating specific genes, such as Irf8.

Original languageEnglish (US)
Pages (from-to)1194-1205
Number of pages12
JournalKidney International
Volume92
Issue number5
DOIs
StatePublished - Nov 2017

Fingerprint

DNA Methylation
Cisplatin
Acute Kidney Injury
Kidney
Wounds and Injuries
Genes
decitabine
Apoptosis
Proximal Kidney Tubule
Nucleic Acid Regulatory Sequences
Cytosine
Methyltransferases
interferon regulatory factor-8
Genetic Promoter Regions
Epigenomics
Knockout Mice
Mammals
Carbon
Genome
Cell Line

Keywords

  • DNA methylation
  • DNA methyltransferases
  • acute kidney injury
  • cisplatin
  • nephrotoxicity

ASJC Scopus subject areas

  • Nephrology

Cite this

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8. / Guo, Chunyuan; Pei, Lirong; Xiao, Xiao; Wei, QingQing; Chen, Jiankang; Ding, Hanfei; Huang, Shuang; Fan, Guoping; Shi, Huidong; Dong, Zheng.

In: Kidney International, Vol. 92, No. 5, 11.2017, p. 1194-1205.

Research output: Contribution to journalArticle

@article{6b6292fe1145408b91f18b8cefe3fae8,
title = "DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8",
abstract = "DNA methylation is an epigenetic mechanism that regulates gene transcription without changing primary nucleotide sequences. In mammals, DNA methylation involves the covalent addition of a methyl group to the 5-carbon position of cytosine by DNA methyltransferases (DNMTs). The change of DNA methylation and its pathological role in acute kidney injury (AKI) remain largely unknown. Here, we analyzed genome-wide DNA methylation during cisplatin-induced AKI by reduced representation bisulfite sequencing. This technique identified 215 differentially methylated regions between the kidneys of control and cisplatin-treated animals. While most of the differentially methylated regions were in the intergenic, intronic, and coding DNA sequences, some were located in the promoter or promoter-regulatory regions of 15 protein-coding genes. To determine the pathological role of DNA methylation, we initially examined the effects of the DNA methylation inhibitor 5-aza-2'-deoxycytidine and showed it increased cisplatin-induced apoptosis in a rat kidney proximal tubular cell line. We further established a kidney proximal tubule-specific DNMT1 (PT-DNMT1) knockout mouse model, which showed more severe AKI during cisplatin treatment than wild-type mice. Finally, interferon regulatory factor 8 (Irf8), a pro-apoptotic factor, was identified as a hypomethylated gene in cisplatin-induced AKI, and this hypomethylation was associated with a marked induction of Irf8. In the rat kidney proximal tubular cells, the knockdown of Irf8 suppressed cisplatin-induced apoptosis, supporting a pro-death role of Irf8 in renal tubular cells. Thus, DNA methylation plays a protective role in cisplatin-induced AKI by regulating specific genes, such as Irf8.",
keywords = "DNA methylation, DNA methyltransferases, acute kidney injury, cisplatin, nephrotoxicity",
author = "Chunyuan Guo and Lirong Pei and Xiao Xiao and QingQing Wei and Jiankang Chen and Hanfei Ding and Shuang Huang and Guoping Fan and Huidong Shi and Zheng Dong",
year = "2017",
month = "11",
doi = "10.1016/j.kint.2017.03.038",
language = "English (US)",
volume = "92",
pages = "1194--1205",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

AU - Guo, Chunyuan

AU - Pei, Lirong

AU - Xiao, Xiao

AU - Wei, QingQing

AU - Chen, Jiankang

AU - Ding, Hanfei

AU - Huang, Shuang

AU - Fan, Guoping

AU - Shi, Huidong

AU - Dong, Zheng

PY - 2017/11

Y1 - 2017/11

N2 - DNA methylation is an epigenetic mechanism that regulates gene transcription without changing primary nucleotide sequences. In mammals, DNA methylation involves the covalent addition of a methyl group to the 5-carbon position of cytosine by DNA methyltransferases (DNMTs). The change of DNA methylation and its pathological role in acute kidney injury (AKI) remain largely unknown. Here, we analyzed genome-wide DNA methylation during cisplatin-induced AKI by reduced representation bisulfite sequencing. This technique identified 215 differentially methylated regions between the kidneys of control and cisplatin-treated animals. While most of the differentially methylated regions were in the intergenic, intronic, and coding DNA sequences, some were located in the promoter or promoter-regulatory regions of 15 protein-coding genes. To determine the pathological role of DNA methylation, we initially examined the effects of the DNA methylation inhibitor 5-aza-2'-deoxycytidine and showed it increased cisplatin-induced apoptosis in a rat kidney proximal tubular cell line. We further established a kidney proximal tubule-specific DNMT1 (PT-DNMT1) knockout mouse model, which showed more severe AKI during cisplatin treatment than wild-type mice. Finally, interferon regulatory factor 8 (Irf8), a pro-apoptotic factor, was identified as a hypomethylated gene in cisplatin-induced AKI, and this hypomethylation was associated with a marked induction of Irf8. In the rat kidney proximal tubular cells, the knockdown of Irf8 suppressed cisplatin-induced apoptosis, supporting a pro-death role of Irf8 in renal tubular cells. Thus, DNA methylation plays a protective role in cisplatin-induced AKI by regulating specific genes, such as Irf8.

AB - DNA methylation is an epigenetic mechanism that regulates gene transcription without changing primary nucleotide sequences. In mammals, DNA methylation involves the covalent addition of a methyl group to the 5-carbon position of cytosine by DNA methyltransferases (DNMTs). The change of DNA methylation and its pathological role in acute kidney injury (AKI) remain largely unknown. Here, we analyzed genome-wide DNA methylation during cisplatin-induced AKI by reduced representation bisulfite sequencing. This technique identified 215 differentially methylated regions between the kidneys of control and cisplatin-treated animals. While most of the differentially methylated regions were in the intergenic, intronic, and coding DNA sequences, some were located in the promoter or promoter-regulatory regions of 15 protein-coding genes. To determine the pathological role of DNA methylation, we initially examined the effects of the DNA methylation inhibitor 5-aza-2'-deoxycytidine and showed it increased cisplatin-induced apoptosis in a rat kidney proximal tubular cell line. We further established a kidney proximal tubule-specific DNMT1 (PT-DNMT1) knockout mouse model, which showed more severe AKI during cisplatin treatment than wild-type mice. Finally, interferon regulatory factor 8 (Irf8), a pro-apoptotic factor, was identified as a hypomethylated gene in cisplatin-induced AKI, and this hypomethylation was associated with a marked induction of Irf8. In the rat kidney proximal tubular cells, the knockdown of Irf8 suppressed cisplatin-induced apoptosis, supporting a pro-death role of Irf8 in renal tubular cells. Thus, DNA methylation plays a protective role in cisplatin-induced AKI by regulating specific genes, such as Irf8.

KW - DNA methylation

KW - DNA methyltransferases

KW - acute kidney injury

KW - cisplatin

KW - nephrotoxicity

UR - http://www.scopus.com/inward/record.url?scp=85023170776&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85023170776&partnerID=8YFLogxK

U2 - 10.1016/j.kint.2017.03.038

DO - 10.1016/j.kint.2017.03.038

M3 - Article

C2 - 28709638

AN - SCOPUS:85023170776

VL - 92

SP - 1194

EP - 1205

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 5

ER -