論文 - 新井 良和
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Arai Y., Nishino K.
Journal of Toxicological Sciences 48 ( 11 ) 571 - 583 2023年9月
担当区分：筆頭著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Toxicological Sciences
Various chemicals, including pesticides, heavy metals, and metabolites of tobacco, have been detected in fetal environment. Fetuses are exposed to these chemicals at relatively low concentrations; however, their risk of developing neurological and behavioral disorders increases after birth. We aimed to evaluate the effects of five chemicals (diethylphosphate, cotinine, octachlorodipropyl ether, mercury, and selenium) detected in the serum of pregnant mothers on neural development using human neurospheres (NSphs) differentiated from induced pluripotent stem cells. Exposure to each chemical at serum concentrations revealed no effects on NSph development. However, combined exposure to the five chemicals caused a significant decrease in NSph size and altered gene expression and neural differentiation. Thus, we next focused on DNA methylation to investigate changes in NSph properties caused by chemical exposure. Combined exposure to chemicals had extremely small effects on the DNA methylation status of NSphs at individual gene loci. However, stochastic changes in methylation status caused by chemical exposure were significantly accumulated throughout the entire genome. These results suggest that the five chemicals acted as epimutagens that alter the epigenetic status during human neural development at the biological level. Taken together, we showed for the first time, the epimutagen-induced alterations in neural differentiation at serum concentrations using an in vitro human neuronal model.
DOI： 10.2131/jts.48.571
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Sekiya A., Takasawa K., Arai Y., Horike S.i., Akutsu H., Umezawa A., Nishino K.
Regenerative Therapy 21 620 - 630 2022年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Regenerative Therapy
Introduction: Human induced pluripotent stem cells (hiPSCs) are useful tools for reproducing neural development in vitro. However, each hiPSC line has a different ability to differentiate into specific lineages, known as differentiation propensity, resulting in reduced reproducibility and increased time and funding requirements for research. To overcome this issue, we searched for predictive signatures of neural differentiation propensity of hiPSCs focusing on DNA methylation, which is the main modulator of cellular properties. Methods: We obtained 32 hiPSC lines and their comprehensive DNA methylation data using the Infinium MethylationEPIC BeadChip. To assess the neural differentiation efficiency of these hiPSCs, we measured the percentage of neural stem cells on day 7 of induction. Using the DNA methylation data of undifferentiated hiPSCs and their measured differentiation efficiency into neural stem cells as the set of data, and HSIC Lasso, a machine learning-based nonlinear feature selection method, we attempted to identify neural differentiation-associated differentially methylated sites. Results: Epigenome-wide unsupervised clustering cannot distinguish hiPSCs with varying differentiation efficiencies. In contrast, HSIC Lasso identified 62 CpG sites that could explain the neural differentiation efficiency of hiPSCs. Features selected by HSIC Lasso were particularly enriched within 3 Mbp of chromosome 5, harboring IRX1, IRX2, and C5orf38 genes. Within this region, DNA methylation rates were correlated with neural differentiation efficiency and were negatively correlated with gene expression of the IRX1/2 genes, particularly in female hiPSCs. In addition, forced expression of the IRX1/2 impaired the neural differentiation ability of hiPSCs in both sexes. Conclusion: We for the first time showed that the DNA methylation state of the IRX1/2 genes of hiPSCs is a predictive biomarker of their potential for neural differentiation. The predictive markers for neural differentiation efficiency identified in this study may be useful for the selection of suitable undifferentiated hiPSCs prior to differentiation induction.
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Nishino K, Arai Y 他
Human Cell 34 ( 1 ) 99 - 110 2021年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Human Cell
The use of human induced pluripotent stem cells (iPSCs), used as an alternative to human embryonic stem cells (ESCs), is a potential solution to challenges, such as immune rejection, and does not involve the ethical issues concerning the use of ESCs in regenerative medicine, thereby enabling developments in biological research. However, comparative analyses from previous studies have not indicated any specific feature that distinguishes iPSCs from ESCs. Therefore, in this study, we established a linear classification-based learning model to distinguish among ESCs, iPSCs, embryonal carcinoma cells (ECCs), and somatic cells on the basis of their DNA methylation profiles. The highest accuracy achieved by the learned models in identifying the cell type was 94.23%. In addition, the epigenetic signature of iPSCs, which is distinct from that of ESCs, was identified by component analysis of the learned models. The iPSC-specific regions with methylation fluctuations were abundant on chromosomes 7, 8, 12, and 22. The method developed in this study can be utilized with comprehensive data and widely applied to many aspects of molecular biology research.
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Dog steroidogenic factor-1: molecular cloning and analysis of epigenetic regulation.
Sekiya A, Takasawa K, Arai Y, Torisu S, Nishino K
The Journal of veterinary medical science 2020年4月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：公益社団法人 日本獣医学会
Steroidogenic factor 1 (SF-1) is a nuclear receptor that is important in steroid hormone production, and adrenal and gonad development. The <i>SF-1</i> gene is highly conserved among most vertebrates. However, dog <i>SF-1</i> registered in public databases, such as CanFam3.1, lacks the 5′ end compared to other mammals including mouse, human, bovine, and cat. Whether this defect is due to species differences or database error is unclear. Here, we determined the full-length dog <i>SF-1</i> cDNA sequence and identified the missing 5′ end sequence in the databases. The coding region of the dog <i>SF-1</i> gene has 1,386 base pairs, and the protein has 461 amino acid residues. Sequence alignment analysis among vertebrates revealed that the 5′ end sequence of dog <i>SF-1</i> cDNA is highly conserved compared to other vertebrates. The genomic position of the first exon was determined, and its promoter region sequence was analyzed. The DNA methylation state at the basal promoter and the expression of dog <i>SF-1</i> in steroidogenic tissues and non-steroidogenic cells were examined. CpG sites at the basal promoter displayed methylation kinetics inversely correlated with gene expression. The promoter was hypomethylated and hypermethylated in <i>SF-1</i> expressing and non-<i>SF-1</i> expressing tissues, respectively. In conclusion, we identified the true full sequence of dog <i>SF-1 </i>cDNA and determined the genome sequence around the first exon. The gene is under the control of epigenetic regulation, such as DNA methylation, at the promoter.
DOI： 10.1292/jvms.20-0050
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DNA methylation ambiguity in the Fibrillin-1 (FBN1) CpG island shore possibly involved in Marfan syndrome.
Arai Y, Umeyama K, Okazaki N, Nakano K, Nishino K, Nagashima H, Ohgane J
Scientific reports 10 ( 1 ) 5287 2020年3月
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Epigenetic-scale comparison of human iPSCs generated by retrovirus, Sendai virus or episomal vectors. 査読あり
Nishino K, Arai Y, Takasawa K, Toyoda M, Yamazaki-Inoue M, Sugawara T, Akutsu H, Nishimura K, Ohtaka M, Nakanishi M, Umezawa A
Regenerative therapy 9 71 - 78 2018年12月
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Effectiveness of bioengineered islet cell sheets for the treatment of diabetes mellitus 査読あり
Nagaya M, Katsumata Y, Arai Y, Umeki I, Nakano K, Kasai Y, Hasegawa K, Okamoto K, Itazaki S, Matsunari H, Watanabe M, Umeyama K, Nagashima H
J Surg Res 227 119 - 129 2018年7月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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DNA methylation enhanced telomerase reverse transcriptase expression in human-induced pluripotent stem cells. 査読あり
Takasawa K, Arai Y, Yamazaki-inoue M, Toyoda M, Akutsu H, Umezawa A, Nishino K
Hum Cell 31 ( 1 ) 78 - 86 2018年1月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Evidence of exposure to chemicals and heavy metals during pregnancy in Japanese women
Maekawa R., Ito R., Iwasaki Y., Saito K., Akutsu K., Takatori S., Ishii R., Kondo F., Arai Y., Ohgane J., Shiota K., Makino T., Sugino N.
Reproductive Medicine and Biology 16 ( 4 ) 337 - 348 2017年10月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Reproductive Medicine and Biology
© 2017 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine. Purpose: Prenatal exposure to environmental chemicals is a growing concern, because such exposures have been shown to be associated with various diseases. The levels of chemicals and heavy metals in maternal blood, cord blood, maternal urine and amniotic fluid in Japanese pregnant women were investigated. Methods: A total of 145 women, including 14 fetal growth restriction cases, were included in the present study. The levels of phthalates (di[2-ethylhexyl]phthalate and mono[2-ethylhexyl]phthalate), perfluorinated compounds (perfluorooctane sulfonate, perfluorohexanoic acid, perfluorooctanoic acid, and perfluorononanoic acid), pesticides (dimethylphosphate, dimethylthiophosphate, diethylphosphate, diethylthiophosphate, 3-phenoxybenzoic acid, and octachlorodipropyl ether), bisphenol A, nicotine (nicotine, nornicotine, cotinine, norcotinine, and trans-3’-hydroxycotinine), polybrominated diphenyl ethers, and heavy metals were measured. The relationship between fetal growth and the levels of chemicals and heavy metals were investigated. Results: Phthalates, perfluorinated compounds, pesticides, polybrominated diphenyl ethers, and heavy metals were detected in high frequency, whereas nicotine and bisphenol A were almost negative. Phthalates, perfluorinated compounds, and several heavy metals were transferred to the fetus. High perfluorononanoic acid levels in the maternal blood and cord blood, and low perfluorooctanoic acid level in the cord blood were significantly and negatively associated with fetal growth. Conclusions: The present study showed that pregnant women in Japan and their fetuses are exposed to a variety of chemicals and heavy metals.
DOI： 10.1002/rmb2.12049
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Establishment of DNA methylation patterns of the Fibrillin1 (FBN1) gene in porcine embryos and tissues. 査読あり
Yoshikazu Arai,他
Journal of Reproduction and Development 2017年4月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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A transgenic-cloned pig model expressing non-fluorescent modified Plum. 査読あり
Masaki Nagaya,Yoshikazu Arai,他
Journal of Reproduction and Development 2016年10月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Ultra-Deep Bisulfite Sequencing to Detect Specific DNA Methylation Patterns of Minor Cell Types in Heterogeneous Cell Populations: An Example of the Pituitary Tissue. 査読あり
Yoshikazu Arai,他
PLoS One 2016年1月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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A new system to evaluate the influence of immunosuppressive drugs on pancreatic islets using epigenetic analysis in a 3-dimensional culture.
Nagaya M, Arai Y, Matsunari H, Honda M, Nakano K, Maehara M, Sugimoto N, Kobayashi M, Sakai R, Asano Y, Watanabe M, Umeyama K, Nagashima H
Pancreas 44 ( 5 ) 778 - 85 2015年7月
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Putative Epimutagens in Maternal Peripheral and Cord Blood Samples Identified Using Human Induced Pluripotent Stem Cells.
Arai Y, Hayakawa K, Arai D, Ito R, Iwasaki Y, Saito K, Akutsu K, Takatori S, Ishii R, Hayashi R, Izumi S, Sugino N, Kondo F, Horie M, Nakazawa H, Makino T, Hirosawa M, Shiota K, Ohgane J
BioMed research international 2015 876047 2015年
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DNA methylation profiles provide a viable index for porcine pluripotent stem cells.
Arai Y, Ohgane J, Fujishiro SH, Nakano K, Matsunari H, Watanabe M, Umeyama K, Azuma D, Uchida N, Sakamoto N, Makino T, Yagi S, Shiota K, Hanazono Y, Nagashima H
Genesis (New York, N.Y. : 2000) 51 ( 11 ) 763 - 76 2013年11月
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Generation of naive-like porcine-induced pluripotent stem cells capable of contributing to embryonic and fetal development.
Fujishiro SH, Nakano K, Mizukami Y, Azami T, Arai Y, Matsunari H, Ishino R, Nishimura T, Watanabe M, Abe T, Furukawa Y, Umeyama K, Yamanaka S, Ema M, Nagashima H, Hanazono Y
Stem cells and development 22 ( 3 ) 473 - 82 2013年2月
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Generating porcine chimeras using inner cell mass cells and parthenogenetic preimplantation embryos.
Nakano K, Watanabe M, Matsunari H, Matsuda T, Honda K, Maehara M, Kanai T, Hayashida G, Kobayashi M, Kuramoto M, Arai Y, Umeyama K, Fujishiro SH, Mizukami Y, Nagaya M, Hanazono Y, Nagashima H
PloS one 8 ( 4 ) e61900 2013年
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Generation of interleukin-2 receptor gamma gene knockout pigs from somatic cells genetically modified by zinc finger nuclease-encoding mRNA.
Watanabe M, Nakano K, Matsunari H, Matsuda T, Maehara M, Kanai T, Kobayashi M, Matsumura Y, Sakai R, Kuramoto M, Hayashida G, Asano Y, Takayanagi S, Arai Y, Umeyama K, Nagaya M, Hanazono Y, Nagashima H
PloS one 8 ( 10 ) e76478 2013年
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Non-CpG methylation occurs in the regulatory region of the Sry gene.
Nishino K, Hattori N, Sato S, Arai Y, Tanaka S, Nagy A, Shiota K
The Journal of reproduction and development 57 ( 5 ) 586 - 93 2011年10月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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Epigenetic assessment of environmental chemicals detected in maternal peripheral and cord blood samples.
Arai Y, Ohgane J, Yagi S, Ito R, Iwasaki Y, Saito K, Akutsu K, Takatori S, Ishii R, Hayashi R, Izumi S, Sugino N, Kondo F, Horie M, Nakazawa H, Makino T, Shiota K
The Journal of reproduction and development 57 ( 4 ) 507 - 17 2011年9月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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TIF1beta regulates the pluripotency of embryonic stem cells in a phosphorylation-dependent manner.
Seki Y, Kurisaki A, Watanabe-Susaki K, Nakajima Y, Nakanishi M, Arai Y, Shiota K, Sugino H, Asashima M
Proceedings of the National Academy of Sciences of the United States of America 107 ( 24 ) 10926 - 31 2010年6月
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Genome-wide DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) residing in mouse pluripotent stem cells.
Sato S, Yagi S, Arai Y, Hirabayashi K, Hattori N, Iwatani M, Okita K, Ohgane J, Tanaka S, Wakayama T, Yamanaka S, Shiota K
Genes to cells : devoted to molecular & cellular mechanisms 15 ( 6 ) 607 - 18 2010年6月
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A new class of tissue-specifically methylated regions involving entire CpG islands in the mouse.
Suzuki M, Sato S, Arai Y, Shinohara T, Tanaka S, Greally JM, Hattori N, Shiota K
Genes to cells : devoted to molecular & cellular mechanisms 12 ( 12 ) 1305 - 14 2007年12月
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PGC7/Stella protects against DNA demethylation in early embryogenesis.
Nakamura T, Arai Y, Umehara H, Masuhara M, Kimura T, Taniguchi H, Sekimoto T, Ikawa M, Yoneda Y, Okabe M, Tanaka S, Shiota K, Nakano T
Nature cell biology 9 ( 1 ) 64 - 71 2007年1月
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DNA methylation errors in cloned mice disappear with advancement of aging.
Senda S,Wakayama T,Arai Y,Yamazaki Y,Ohgane J, Tanaka S, Yanagimachi R,Shiota K
Cloning and Stem Cells 2007年
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Stage-by-stage change in DNA methylation status of Dnmt1 locus during mouse early development.
Ko YG, Nishino K, Hattori N, Arai Y, Tanaka S, Shiota K
The Journal of biological chemistry 280 ( 10 ) 9627 - 34 2005年3月