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; Ken Ei Sada; Jun Wada

doi:10.1038/s41598-019-38809-y

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, Ken Ei Sada, Jun Wada

Research output: Contribution to journal › Article › peer-review

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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 language	English
Article number	3054
Pages (from-to)	3054
Journal	Scientific reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-38809-y
Publication status	Published - Feb 28 2019
Externally published	Yes

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Hiramatsu, S., Watanabe, K. S., Zeggar, S., Asano, Y., Miyawaki, Y., Yamamura, Y., Katsuyama, E., Katsuyama, T., Watanabe, H., Takano-Narazaki, M., Matsumoto, Y., Kawabata, T., Sada, K. E., & Wada, J. (2019). Regulation of Cathepsin E gene expression by the transcription factor Kaiso in MRL/lpr mice derived CD4+ T cells. Scientific reports, 9(1), 3054. [3054]. https://doi.org/10.1038/s41598-019-38809-y

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, Ken Ei; Wada, Jun.

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

Research output: Contribution to journal › Article › peer-review

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, KE & 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, Ken Ei ; 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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title = "Regulation of Cathepsin E gene expression by the transcription factor Kaiso in MRL/lpr mice derived CD4+ T cells",

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.",

author = "Sumie Hiramatsu and Watanabe, {Katsue S.} and Sonia Zeggar and Yosuke Asano and Yoshia Miyawaki and Yuriko Yamamura and Eri Katsuyama and Takayuki Katsuyama and Haruki Watanabe and Mariko Takano-Narazaki and Yoshinori Matsumoto and Tomoko Kawabata and Sada, {Ken Ei} and Jun Wada",

note = "Funding Information: Competing Interests: K.S. receives speaker honoraria from Chugai Pharma. J.W. receives speaker honoraria from Daiichi Sankyo, M.S.D., Tanabe Mitsubishi, Taisho Toyama and receives grant support from Baxter, Dainippon Sumitomo, Ono, and Teijin Pharma. Funding Information: We thank Ms. Yoshiko Hada at Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Ms. Sumire Ishihara at Department of Animal Resources, Advanced Science Research Center, Okayama University for excellent technical support. Funding: This work was supported by JSPS Grant-in-Aid for Scientific Research, Grant numbers (16K09895, 16K09896, 16K19601, 16K19602, 16K19600, 17K09976, 18K16151). Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = feb,

day = "28",

doi = "10.1038/s41598-019-38809-y",

language = "English",

volume = "9",

pages = "3054",

journal = "Scientific Reports",

issn = "2045-2322",

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number = "1",

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TY - JOUR

T1 - Regulation of Cathepsin E gene expression by the transcription factor Kaiso in MRL/lpr mice derived CD4+ T cells

AU - Hiramatsu, Sumie

AU - Watanabe, Katsue S.

AU - Zeggar, Sonia

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, Ken Ei

AU - Wada, Jun

N1 - Funding Information: Competing Interests: K.S. receives speaker honoraria from Chugai Pharma. J.W. receives speaker honoraria from Daiichi Sankyo, M.S.D., Tanabe Mitsubishi, Taisho Toyama and receives grant support from Baxter, Dainippon Sumitomo, Ono, and Teijin Pharma. Funding Information: We thank Ms. Yoshiko Hada at Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Ms. Sumire Ishihara at Department of Animal Resources, Advanced Science Research Center, Okayama University for excellent technical support. Funding: This work was supported by JSPS Grant-in-Aid for Scientific Research, Grant numbers (16K09895, 16K09896, 16K19601, 16K19602, 16K19600, 17K09976, 18K16151). Publisher Copyright: © 2019, The Author(s).

PY - 2019/2/28

Y1 - 2019/2/28

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

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