Regulation of Cathepsin E gene expression by the transcription factor Kaiso in MRL/lpr mice derived CD4+ T cells

Sumie Hiramatsu, Katsue S. Watanabe, Sonia Zeggar, Yosuke Asano, Yoshia Miyawaki, Yuriko Yamamura, Eri Katsuyama, Takayuki Katsuyama, Haruki Watanabe, Mariko Takano-Narazaki, Yoshinori Matsumoto, Tomoko Kawabata, Kenei Sada, Jun Wada

Research output: Contribution to journalArticle

Abstract

Global DNA hypomethylation in CD4+ cells in systemic lupus erythematosus (SLE) was suggested to play a key role in the pathogenesis. To identify new methylation-sensitive genes, we integrated genome-wide DNA methylation and mRNA profiling data in CD4+ cells of MRL/lpr (MRL) and C57BL6/J (B6) mice. We identified Cathepsin E (Ctse), in which 13 methyl-CpGs within 583 bp region of intron 1 were hypomethylated, and Ctse mRNA upregulated in MRL compared with B6 mice. One of methyl-CpGs, mCGCG was 93.3 ± 2.05% methylated in B6 mice, while 80.0 ± 6.2% methylated and mutated to CGGG in MRL mice. Kaiso is known to bind to mCGCG and we hypothesized that it represses expression of Ctse in B6 mice. The binding of Kaiso to mCGCG site in B6 mice was reduced in MRL mice revealed by ChIP-PCR. EL4 cells treated with 5-azaC and/or Trichostatin A showed the suppression of binding of Kaiso to mCGCG motif by ChIP-PCR and the overexpression of Ctse was demonstrated by qPCR. Ctse gene silencing by siRNA in EL4 cells resulted in reduction of IL-10 secretion. The hypomethylation of mCGCG motif, reduced recruitment of Kaiso, and increased expression of Ctse and Il-10 in CD4+ cells may be involved in the pathogenesis of SLE.

Original languageEnglish
Article number3054
Pages (from-to)3054
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - Feb 28 2019

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Cathepsin E
Inbred MRL lpr Mouse
Transcription Factors
T-Lymphocytes
Gene Expression
Systemic Lupus Erythematosus
trichostatin A
Polymerase Chain Reaction
Messenger RNA
Gene Silencing
DNA Methylation
Interleukin-10
Introns
Methylation
Small Interfering RNA
Genome

ASJC Scopus subject areas

  • General

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Regulation of Cathepsin E gene expression by the transcription factor Kaiso in MRL/lpr mice derived CD4+ T cells. / Hiramatsu, Sumie; Watanabe, Katsue S.; Zeggar, Sonia; Asano, Yosuke; Miyawaki, Yoshia; Yamamura, Yuriko; Katsuyama, Eri; Katsuyama, Takayuki; Watanabe, Haruki; Takano-Narazaki, Mariko; Matsumoto, Yoshinori; Kawabata, Tomoko; Sada, Kenei; Wada, Jun.

In: Scientific reports, Vol. 9, No. 1, 3054, 28.02.2019, p. 3054.

Research output: Contribution to journalArticle

Hiramatsu, S, Watanabe, KS, Zeggar, S, Asano, Y, Miyawaki, Y, Yamamura, Y, Katsuyama, E, Katsuyama, T, Watanabe, H, Takano-Narazaki, M, Matsumoto, Y, Kawabata, T, Sada, K & Wada, J 2019, 'Regulation of Cathepsin E gene expression by the transcription factor Kaiso in MRL/lpr mice derived CD4+ T cells', Scientific reports, vol. 9, no. 1, 3054, pp. 3054. https://doi.org/10.1038/s41598-019-38809-y
Hiramatsu, Sumie ; Watanabe, Katsue S. ; Zeggar, Sonia ; Asano, Yosuke ; Miyawaki, Yoshia ; Yamamura, Yuriko ; Katsuyama, Eri ; Katsuyama, Takayuki ; Watanabe, Haruki ; Takano-Narazaki, Mariko ; Matsumoto, Yoshinori ; Kawabata, Tomoko ; Sada, Kenei ; Wada, Jun. / Regulation of Cathepsin E gene expression by the transcription factor Kaiso in MRL/lpr mice derived CD4+ T cells. In: Scientific reports. 2019 ; Vol. 9, No. 1. pp. 3054.
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AU - Asano, Yosuke

AU - Miyawaki, Yoshia

AU - Yamamura, Yuriko

AU - Katsuyama, Eri

AU - Katsuyama, Takayuki

AU - Watanabe, Haruki

AU - Takano-Narazaki, Mariko

AU - Matsumoto, Yoshinori

AU - Kawabata, Tomoko

AU - Sada, Kenei

AU - Wada, Jun

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N2 - Global DNA hypomethylation in CD4+ cells in systemic lupus erythematosus (SLE) was suggested to play a key role in the pathogenesis. To identify new methylation-sensitive genes, we integrated genome-wide DNA methylation and mRNA profiling data in CD4+ cells of MRL/lpr (MRL) and C57BL6/J (B6) mice. We identified Cathepsin E (Ctse), in which 13 methyl-CpGs within 583 bp region of intron 1 were hypomethylated, and Ctse mRNA upregulated in MRL compared with B6 mice. One of methyl-CpGs, mCGCG was 93.3 ± 2.05% methylated in B6 mice, while 80.0 ± 6.2% methylated and mutated to CGGG in MRL mice. Kaiso is known to bind to mCGCG and we hypothesized that it represses expression of Ctse in B6 mice. The binding of Kaiso to mCGCG site in B6 mice was reduced in MRL mice revealed by ChIP-PCR. EL4 cells treated with 5-azaC and/or Trichostatin A showed the suppression of binding of Kaiso to mCGCG motif by ChIP-PCR and the overexpression of Ctse was demonstrated by qPCR. Ctse gene silencing by siRNA in EL4 cells resulted in reduction of IL-10 secretion. The hypomethylation of mCGCG motif, reduced recruitment of Kaiso, and increased expression of Ctse and Il-10 in CD4+ cells may be involved in the pathogenesis of SLE.

AB - Global DNA hypomethylation in CD4+ cells in systemic lupus erythematosus (SLE) was suggested to play a key role in the pathogenesis. To identify new methylation-sensitive genes, we integrated genome-wide DNA methylation and mRNA profiling data in CD4+ cells of MRL/lpr (MRL) and C57BL6/J (B6) mice. We identified Cathepsin E (Ctse), in which 13 methyl-CpGs within 583 bp region of intron 1 were hypomethylated, and Ctse mRNA upregulated in MRL compared with B6 mice. One of methyl-CpGs, mCGCG was 93.3 ± 2.05% methylated in B6 mice, while 80.0 ± 6.2% methylated and mutated to CGGG in MRL mice. Kaiso is known to bind to mCGCG and we hypothesized that it represses expression of Ctse in B6 mice. The binding of Kaiso to mCGCG site in B6 mice was reduced in MRL mice revealed by ChIP-PCR. EL4 cells treated with 5-azaC and/or Trichostatin A showed the suppression of binding of Kaiso to mCGCG motif by ChIP-PCR and the overexpression of Ctse was demonstrated by qPCR. Ctse gene silencing by siRNA in EL4 cells resulted in reduction of IL-10 secretion. The hypomethylation of mCGCG motif, reduced recruitment of Kaiso, and increased expression of Ctse and Il-10 in CD4+ cells may be involved in the pathogenesis of SLE.

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