2021/10/29 更新

写真a

オオタニ ヒトシ
大谷仁志
OHTANI Hitoshi
所属
大学院生命農学研究科 動物科学専攻 動物科学 助教
大学院担当
大学院生命農学研究科
学部担当
農学部 資源生物科学科
職名
助教

学位 1

  1. 博士(理学) ( 2011年3月   東京医科歯科大学 ) 

研究キーワード 6

  1. Non-coding RNA

  2. Genome evolution

  3. Epigenome

  4. Endogenous retrovirus

  5. Cancer therapy

  6. Bioinformatics

研究分野 1

  1. ライフサイエンス / ゲノム生物学

経歴 3

  1. 名古屋大学大学院   生命農学研究科動物科学専攻

    2020年4月 - 現在

  2. Van Andel Research Institute   Center of Epigenetics   PostDoc

    2014年5月 - 2020年3月

  3. 慶應義塾大学   医学部

    2011年4月 - 2014年5月

学歴 1

  1. 東京医科歯科大学   生命情報科学教育部

    2005年4月 - 2011年3月

受賞 2

  1. AACR Annual Meeting Scholar-in-Training Award

    2018年4月   AACR  

    大谷仁志

  2. Academic awards of Japanese Society for Histocompatibility and Immunogenetics

    2006年9月   Japanese Society for Histocompatibility and Immunogenetics  

    大谷仁志

 

論文 22

  1. Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity are Linked to Clinical Responses to 5-Azacytidine. 査読有り 国際誌

    Hitoshi Ohtani, Andreas Due Ørskov, Alexandra S Helbo, Linn Gillberg, Minmin Liu, Wanding Zhou, Johanna Ungerstedt, Eva Hellström-Lindberg, Weili Sun, Gangning Liang, Peter A Jones, Kirsten Grønbæk

    Cancer research     2020年4月

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    記述言語:英語  

    The DNA methyltransferase inhibitors (DNMTi) 5-azacytidine (AZA) and 5-aza-2-deoxycytidine have been approved for the treatment of different types of hematological malignancies. However, only about 50% of patients respond to treatment. Therefore, a more comprehensive understanding of the molecular changes in patients treated with DNMTi is needed. Here we examined gene expression profiles in a total of 150 RNA samples from two adult cohorts and one pediatric cohort with hematological cancers taken before, during, and after treatment with AZA (40 patients; 15 non-responders, 25 responders). Using each patient as their own control, malignant cells showed preferential activation of a subset of evolutionarily young transposable elements (TE), including endogenous retroviral long terminal repeats (LTR), short and long interspersed nuclear elements (SINE and LINE), and the type I interferon (IFN) pathway in responders, all independent of disease classification. Transfection of eight upregulated LTR into recipient human cells in culture showed robust and heterogenous activation of six genes in the type I IFN pathway. These results, obtained in diverse hematological disease entities, show that common targets (TE) activated by the same drug (AZA) elicit an immune response which may be important for patient's responses to DNMTi.

    DOI: 10.1158/0008-5472.CAN-19-1696

    PubMed

  2. Switching roles for DNA and histone methylation depend on evolutionary ages of human endogenous retroviruses. 査読有り

    Ohtani H, Liu M, Zhou W, Liang G, Jones PA

    Genome research   28 巻 ( 8 ) 頁: 1147 - 1157   2018年8月

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  3. Vitamin C increases viral mimicry induced by 5-aza-2 '-deoxycytidine 査読有り

    Minmin Liu, Hitoshi Ohtani, Wanding Zhou, Andreas Due Orskov, Jessica Charlet, Yang W. Zhang, Hui Shen, Stephen B. Baylin, Gangning Liang, Kirsten Gronbaek, Peter A. Jones

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   113 巻 ( 37 ) 頁: 10238 - 10244   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    Vitamin C deficiency is found in patients with cancer and might complicate various therapy paradigms. Here we show how this deficiency may influence the use of DNA methyltransferase inhibitors (DNMTis) for treatment of hematological neoplasias. In vitro, when vitamin C is added at physiological levels to low doses of the DNMTi 5-aza-2'-deoxycytidine (5-aza-CdR), there is a synergistic inhibition of cancer-cell proliferation and increased apoptosis. These effects are associated with enhanced immune signals including increased expression of bidirectionally transcribed endogenous retrovirus (ERV) transcripts, increased cytosolic dsRNA, and activation of an IFN-inducing cellular response. This synergistic effect is likely the result of both passive DNA demethylation by DNMTi and active conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) enzymes at LTR regions of ERVs, because vitamin C acts as a cofactor for TET proteins. In addition, TET2 knockout reduces the synergy between the two compounds. Furthermore, we show that many patients with hematological neoplasia are markedly vitamin C deficient. Thus, our data suggest that correction of vitamin C deficiency in patients with hematological and other cancers may improve responses to epigenetic therapy with DNMTis.

    DOI: 10.1073/pnas.1612262113

    Web of Science

    PubMed

  4. DmGTSF1 is necessary for Piwi-piRISC-mediated transcriptional transposon silencing in the Drosophila ovary 査読有り

    Hitoshi Ohtani, Yuka W. Iwasaki, Aoi Shibuya, Haruhiko Siomi, Mikiko C. Siomi, Kuniaki Saito

    GENES & DEVELOPMENT   27 巻 ( 15 ) 頁: 1656 - 1661   2013年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT  

    The Piwi-piRNA (PIWI-interacting RNA) complex (Piwi-piRISC) in Drosophila ovarian somatic cells represses transposons transcriptionally to maintain genome integrity; however, the underlying mechanisms remain obscure. Here, we reveal that DmGTSF1, a Drosophila homolog of gametocyte-specific factor 1 (GTSF1) (which is required for transposon silencing in mouse testes), is necessary for Piwi-piRISC to repress target transposons and neighboring genes. DmGTSF1 depletion affected neither piRNA biogenesis nor nuclear import of Piwi-piRISC. DmGTSF1 mutations caused derepression of transposons and loss of ovary follicle layers, resulting in female infertility. We suggest that DmGTSF1, a nuclear Piwi interactor, is an integral factor in Piwi-piRISC-mediated transcriptional silencing.

    DOI: 10.1101/gad.221515.113

    Web of Science

    PubMed

  5. Dual EZH2 and G9a inhibition suppresses multiple myeloma cell proliferation by regulating the interferon signal and IRF4-MYC axis 査読有り

    Kazuya Ishiguro, Hiroshi Kitajima, Takeshi Niinuma, Reo Maruyama, Naotaka Nishiyama, Hitoshi Ohtani, Gota Sudo, Mutsumi Toyota, Hajime Sasaki, Eiichiro Yamamoto, Masahiro Kai, Hiroshi Nakase, Hiromu Suzuki

    Cell Death Discovery   7 巻 ( 1 )   2021年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    <title>Abstract</title>Epigenetic mechanisms such as histone modification play key roles in the pathogenesis of multiple myeloma (MM). We previously showed that EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, and G9, a H3K9 methyltransferase, are potential therapeutic targets in MM. Moreover, recent studies suggest EZH2 and G9a cooperate to regulate gene expression. We therefore evaluated the antitumor effect of dual EZH2 and G9a inhibition in MM. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed MM cell proliferation in vitro by inducing cell cycle arrest and apoptosis. Dual EZH2/G9a inhibition also suppressed xenograft formation by MM cells in vivo. In datasets from the Gene Expression Omnibus, higher <italic>EZH2</italic> and <italic>EHMT2</italic> (encoding G9a) expression was significantly associated with poorer prognoses in MM patients. Microarray analysis revealed that EZH2/G9a inhibition significantly upregulated interferon (IFN)-stimulated genes and suppressed IRF4-MYC axis genes in MM cells. Notably, dual EZH2/G9a inhibition reduced H3K27/H3K9 methylation levels in MM cells and increased expression of endogenous retrovirus (ERV) genes, which suggests that activation of ERV genes may induce the IFN response. These results suggest that dual targeting of EZH2 and G9a may be an effective therapeutic strategy for MM.

    DOI: 10.1038/s41420-020-00400-0

    その他リンク: http://www.nature.com/articles/s41420-020-00400-0

  6. Rewiring of chromatin state and gene expression by transposable elements 招待有り 査読有り

    Hitoshi Ohtani, Yuka W. Iwasaki

        2021年4月

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    担当区分:筆頭著者, 責任著者  

  7. Armitage determines Piwi-piRISC processing from precursor formation and quality control to inter-organelle translocation. 査読有り 国際誌

    Haruna Yamashiro, Mayu Negishi, Tatsuki Kinoshita, Hirotsugu Ishizu, Hitoshi Ohtani, Mikiko C Siomi

    EMBO reports   21 巻 ( 2 ) 頁: e48769   2020年2月

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    記述言語:英語  

    Piwi and piRNA form the piRNA-induced silencing complex (piRISC) to repress transposons. In the current model, Armitage (Armi) brings the Piwi-piRISC precursor (pre-piRISC) to mitochondria, where Zucchini-dependent piRISC maturation occurs. Here, we show that Armi is necessary for Piwi-pre-piRISC formation at Yb bodies and that Armi triggers the exit of Piwi-pre-piRISC from Yb bodies and the translocation to mitochondria. Piwi-pre-piRISC resist leaving Yb bodies until Armi binds Piwi-pre-piRISC through the piRNA precursors. The lack of the Armi N-terminus also blocks the Piwi-pre-piRISC exit from Yb bodies. Thus, Armi determines Piwi-piRISC processing, in a multilayered manner, from precursor formation and quality control to inter-organelle translocation for maturation.

    DOI: 10.15252/embr.201948769

    PubMed

  8. Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes. 査読有り 国際誌

    Linn Gillberg, Andreas D Ørskov, Ammar Nasif, Hitoshi Ohtani, Zachary Madaj, Jakob W Hansen, Nicolas Rapin, Johanne B Mogensen, Minmin Liu, Inge H Dufva, Jens Lykkesfeldt, Petra Hajkova, Peter A Jones, Kirsten Grønbæk

    Clinical epigenetics   11 巻 ( 1 ) 頁: 143 - 143   2019年10月

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    記述言語:英語  

    BACKGROUND: Patients with haematological malignancies are often vitamin C deficient, and vitamin C is essential for the TET-induced conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), the first step in active DNA demethylation. Here, we investigate whether oral vitamin C supplementation can correct vitamin C deficiency and affect the 5hmC/5mC ratio in patients with myeloid cancers treated with DNA methyltransferase inhibitors (DNMTis). RESULTS: We conducted a randomized, double-blinded, placebo-controlled pilot trial (NCT02877277) in Danish patients with myeloid cancers performed during 3 cycles of DNMTi-treatment (5-azacytidine, 100 mg/m2/d for 5 days in 28-day cycles) supplemented by oral dose of 500 mg vitamin C (n = 10) or placebo (n = 10) daily during the last 2 cycles. Fourteen patients (70%) were deficient in plasma vitamin C (< 23 μM) and four of the remaining six patients were taking vitamin supplements at inclusion. Global DNA methylation was significantly higher in patients with severe vitamin C deficiency (< 11.4 μM; 4.997 vs 4.656% 5mC relative to deoxyguanosine, 95% CI [0.126, 0.556], P = 0.004). Oral supplementation restored plasma vitamin C levels to the normal range in all patients in the vitamin C arm (mean increase 34.85 ± 7.94 μM, P = 0.0004). We show for the first time that global 5hmC/5mC levels were significantly increased in mononuclear myeloid cells from patients receiving oral vitamin C compared to placebo (0.037% vs - 0.029%, 95% CI [- 0.129, - 0.003], P = 0.041). CONCLUSIONS: Normalization of plasma vitamin C by oral supplementation leads to an increase in the 5hmC/5mC ratio compared to placebo-treated patients and may enhance the biological effects of DNMTis. The clinical efficacy of oral vitamin C supplementation to DNMTis should be investigated in a large randomized, placebo-controlled clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02877277 . Registered on 9 August 2016, retrospectively registered.

    DOI: 10.1186/s13148-019-0739-5

    PubMed

  9. Epigenetic therapy in immune-oncology. 査読有り

    Jones PA, Ohtani H, Chakravarthy A, De Carvalho DD

    Nature reviews. Cancer   19 巻 ( 3 ) 頁: 151 - 161   2019年3月

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  10. Integrative Epigenetic Analysis Reveals Therapeutic Targets to the DNA Methyltransferase Inhibitor Guadecitabine (SGI-110) in Hepatocellular Carcinoma. 査読有り

    Liu M, Zhang L, Li H, Hinoue T, Zhou W, Ohtani H, El-Khoueiry A, Daniels J, O'Connell C, Dorff TB, Lu Q, Weisenberger DJ, Liang G

    Hepatology (Baltimore, Md.)   68 巻 ( 4 ) 頁: 1412 - 1428   2018年10月

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  11. Dual Inhibition of DNA and Histone Methyltransferases Increases Viral Mimicry in Ovarian Cancer Cells. 査読有り

    Liu M, Thomas SL, DeWitt AK, Zhou W, Madaj ZB, Ohtani H, Baylin SB, Liang G, Jones PA

    Cancer research   78 巻 ( 20 ) 頁: 5754 - 5766   2018年10月

  12. APOBEC3H polymorphisms and susceptibility to HIV-1 infection in an Indian population 査読有り

    Taeko K. Naruse, Daisuke Sakurai, Hitoshi Ohtani, Gaurav Sharma, Surendra K. Sharma, Madhu Vajpayee, Narinder K. Mehra, Gurvinder Kaur, Akinori Kimura

    JOURNAL OF HUMAN GENETICS   61 巻 ( 3 ) 頁: 263 - 265   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Human APOBEC3H (A3H) is a member of APOBEC cytidine deaminase family intensively constraining the HIV-1 replication. A3H is known to be polymorphic with different protein stability and anti-HIV-1 activity in vitro. We recently reported that A3H haplotypes composed of two functional polymorphisms, rs139292 (N15del) and rs139297 (G105R), were associated with the susceptibility to HIV-1 infection in Japanese. To confirm the association of A3H and HIV-1 infection in another ethnic group, a total of 241 HIV-1-infected Indian individuals and ethnic-matched 286 healthy controls were analyzed for the A3H polymorphisms. The frequency of 15del allele was high in the HIV-1-infected subjects as compared with the controls (0.477 vs 0.402, odds ratio (OR)=1.36, P=0.014). Haplotype analysis showed that the frequencies of 15del-105R was high (0.475 vs 0.400, OR=1.36, permutation P=0.037) in the HIV-1-infected subjects, confirming the association of A3H polymorphisms with the susceptibility to HIV-1 infection.

    DOI: 10.1038/jhg.2015.136

    Web of Science

    PubMed

  13. APOBEC3H polymorphisms associated with the susceptibility to HIV-1 infection and AIDS progression in Japanese 査読有り

    Daisuke Sakurai, Yasumasa Iwatani, Hitoshi Ohtani, Taeko K. Naruse, Hiroshi Terunuma, Wataru Sugiura, Akinori Kimura

    IMMUNOGENETICS   67 巻 ( 4 ) 頁: 253 - 257   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Human APOBEC3H (A3H) is a member of APOBEC3 cytidine deaminase family that potently restricts HIV-1 replication. Because A3H is genetically divergent with different intracellular stability and anti-HIV-1 activity in vitro, we investigated a possible association of A3H with susceptibility to HIV-1 infection and disease progression in Japanese populations. A total of 191 HIV-1-infected individuals (HIV group), 93 long-term non-progressors to AIDS (LTNP group) and 421 healthy controls were genotyped for two functional APOBEC3H polymorphisms, rs139292 and rs139297. As compared with the controls, minor allele frequency (MAF) for rs139292 was high in the HIV group (MAF in cases vs. controls; 0.322 vs. 0.263, odds ratio (OR) = 1.33, 95 % confidence interval (95 % CI) = 1.02-1.74, p = 0.035) and low in the LTNP group (0.161 vs. 0.263, OR = 0.54, 95 % CI = 0.36-0.82, p = 0.004, pc = 0.007), whereas the MAF for rs139297 was high in the HIV group (0.367 vs. 0.298, OR = 1.36, 95 % CI = 1.07-1.76, p = 0.017, pc = 0.035). In addition, haplotype analyses revealed that the frequencies of A3H-hapC and -hapA were high (0.322 vs. 0.262, OR = 1.33, 95% CI = 1.02-1.74, p = 0.003) and low (0.634 vs. 0.697, OR = 0.75, 95 % CI = 0.58-0.97, p = 0.002), respectively, in the HIV group, whereas the frequencies of A3H-hapC and -hapB were low (0.161 vs. 0.262, OR = 0.54, 95 % CI = 0.36-0.82, p = 0.00003) and high (0.097 vs. 0.040, OR = 2.55, 95 % CI = 1.40-4.62, p = 0.000008), respectively, in the LTNP group, as compared with those in the controls. These observations suggest that the A3H with low anti-HIV-1 activity, A3H-hapC, is associated with the susceptibility to HIV-1 infection, whereas the A3H producing a stable protein, A3H-hapB, may confer a low risk of disease progression to AIDS.

    DOI: 10.1007/s00251-015-0829-2

    Web of Science

    PubMed

  14. Status of TIM-1 exon 4 haplotypes and CD4+T cell counts in HIV-1 seroprevalent North Indians 査読有り

    Gaurav Sharma, Hitoshi Ohtani, Gurvinder Kaur, Taeko K. Naruse, S. K. Sharma, Madhu Vajpayee, Akinori Kimura, Narinder Mehra

    HUMAN IMMUNOLOGY   74 巻 ( 2 ) 頁: 163 - 165   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    The TIM (T cell/transmembrane, immunoglobulin and mucin) proteins are crucial regulators of Th1/Th2 immune responses and have been implicated in several diseases including HIV-1/AIDS. The TIM1 exon 4 that codes for mucin domain is highly diverse, with sequence variants associated with varying phenotypes. In this study, TIM1 exon 4 was sequenced among 227 HIV-1 seroprevalent and 288 healthy non infected individuals from North Indian population and haplotypes established. A novel but rare haplotype D1* was identified among the healthy and differed from D1 by a synonymous substitution G&gt;T at Thr208Thr. The TIM1 haplotype diversity showed no association with susceptibility to HIV-1 infection. The seroprevalent individuals carrying D3A had relatively higher median CD4+T cell counts (368/mu l) than those without (313/mu l; p = 0.02). A comparison of CD4+T counts between D3-A individuals on ART or ART naive did not show any significant difference plausibly due to confounding nature of ART and other factors. (c) 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.humimm.2012.11.013

    Web of Science

    PubMed

  15. Lineage-specific evolution of T-cell immunoglobulin and mucin domain 1 gene in the primates 査読有り

    Hitoshi Ohtani, Taeko K. Naruse, Yuki Iwasaki, Hirofumi Akari, Takafumi Ishida, Tetsuro Matano, Akinori Kimura

    IMMUNOGENETICS   64 巻 ( 9 ) 頁: 669 - 678   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    T-cell immunoglobulin domain and mucin domain containing protein 1 (TIM1), also known as a cellular receptor for hepatitis A virus (HAVCR1) or a molecule induced by ischemic injury in the kidney (KIM1), is involved in the regulation of immune responses. We investigated a natural selection history of TIM1 by comparative sequencing analysis in 24 different primates. It was found that TIM1 had become a pseudogene in multiple lineages of the New World monkey. We also investigated T cell lines originated from four different New World monkey species and confirmed that TIM1 was not expressed at the mRNA level. On the other hand, there were ten amino acid sites in the Ig domain of TIM1 in the other primates, which were suggested to be under positive natural selection. In addition, mucin domain of TIM1 was highly polymorphic in the Old World monkeys, which might be under balanced selection. These data suggested that TIM1 underwent a lineage-specific evolutionary pathway in the primates.

    DOI: 10.1007/s00251-012-0628-y

    Web of Science

    PubMed

  16. Molecular evolution of immunoglobulin superfamily genes in primates 査読有り

    Hitoshi Ohtani, Toshiaki Nakajima, Hirofumi Akari, Takafumi Ishida, Akinori Kimura

    IMMUNOGENETICS   63 巻 ( 7 ) 頁: 417 - 428   2011年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Genes of the immunoglobulin superfamily (IgSF) have a wide variety of cellular activities. In this study, we investigated molecular evolution of IgSF genes in primates by comparing orthologous sequences of 249 IgSF genes among human, chimpanzee, orangutan, rhesus macaque, and common marmoset. To evaluate the non-synonymous/synonymous substitution ratio (omega), we applied Bn-Bs program and PAML program. IgSF genes were classified into 11 functional categories based on the Gene Ontology (GO) database. Among them, IgSF genes in three functional categories, immune system process (GO: 0002376), defense response (GO: 0006952), and multi-organism process (GO: 0051704), which are tightly linked to the regulation of immune system had much higher values of. than genes in the other GO categories. In addition, we estimated the average values of. for each primate lineage. Although each primate lineage had comparable average values of., the human lineage showed the lowest. value for the immune-related genes. Furthermore, 11 IgSF genes, SIGLEC5, SLAMF6, CD33, CD3E, CEACAM8, CD3G, FCER1A, CD48, CD4, TIM4, and FCGR2A, were implied to have been under positive selective pressure during the course of primate evolution. Further sequence analyses of CD3E and CD3G from 23 primate species suggested that the Ig domains of CD3E and CD3G underwent the positive Darwinian selection.

    DOI: 10.1007/s00251-011-0519-7

    Web of Science

    PubMed

  17. No Evidence of an Association between the APOBEC3B Deletion Polymorphism and Susceptibility to HIV Infection and AIDS in Japanese and Indian Populations 査読有り

    Sakiko Itaya, Toshiaki Nakajima, Gurvinder Kaur, Hiroshi Terunuma, Hitoshi Ohtani, Narinder Mehra, Akinori Kimura

    JOURNAL OF INFECTIOUS DISEASES   202 巻 ( 5 ) 頁: 815 - U166   2010年9月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS INC  

    DOI: 10.1086/655227

    Web of Science

    PubMed

  18. TIM1 haplotype may control the disease progression to AIDS in a HIV-1-infected female cohort in Thailand 査読有り

    Nuanjun Wichukchinda, Toshiaki Nakajima, Nongluk Saipradit, Emi E. Nakayama, Hitoshi Ohtani, Archawin Rojanawiwat, Panita Pathipvanich, Koya Ariyoshi, Pathom Sawanpanyalert, Tatsuo Shioda, Akinori Kimura

    AIDS   24 巻 ( 11 ) 頁: 1625 - 1631   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objective: To investigate association of TIM1 sequence variations with HIV/AIDS progression.
    Introduction: HIV-1 infected individuals have wide variations in disease progression including AIDS. T cell immunoglobulin and mucin 1 (TIM1) is a cell surface protein involved in the regulation of Th1/Th2 immune response.
    Materials and methods: We sequenced the highly polymorphic exon 4 of TIM1 from 246 individuals of HIV-1 infected Thai female cohort to determine their TIM1 haplo-types. Associations of TIM1 haplotypes with baseline clinical data (sero-status, plasma viral load, CD4 cell count, and symptomatic AIDS) and survival status during 3 years of follow-up were evaluated.
    Results: Seven TIM1 haplotypes, D3-A, D4, D3-C, D1, W-A, W-C, and D3-C*, were found in the cohort. Patients possessing the D3-A haplotype showed trends towards higher CD4(+) cell count (P=0.06) and lower proportion of AIDS-related symptoms (P=0.022) than the other patients at the baseline. Kaplan-Meier analysis demonstrated that patients carrying the D3-A haplotype had a better survival rates (P=0.019) than the others. D3-A haplotypes was tightly linked to the lower expression levels of TIM1.
    Conclusion: TIM1 D3-A haplotype is associated with the delay of disease progression to AIDS in the HIV-1 infected Thai females. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

    DOI: 10.1097/QAD.0b013e32833a8c6d

    Web of Science

    PubMed

  19. Validation of eight genetic risk factors in East Asian populations replicated the association of BRAP with coronary artery disease 査読有り

    Kunihiko Hinohara, Hitoshi Ohtani, Toshiaki Nakajima, Taishi Sasaoka, Motoji Sawabe, Bok-Soo Lee, Jimin Ban, Jeong-Euy Park, Tohru Izumi, Akinori Kimura

    JOURNAL OF HUMAN GENETICS   54 巻 ( 11 ) 頁: 642 - 646   2009年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Coronary artery disease (CAD) is caused by a thrombotic occlusion or spasm of the coronary artery. Association of genetic variants with susceptibility to CAD has been reported in various populations, but the association should be replicated in other populations to establish the role of genetic variants in CAD. We conducted a case-control study with a total of 1480 CAD cases and 2115 controls from two East Asian populations, Japanese and Korean, to validate the associations of CAD with eight single nucleotide polymorphisms (SNPs) in eight loci, which were identified from large-scale whole-genome association studies in Europeans or East Asians. Among the tested SNPs, one SNP in BRAP (rs11066001) showed a significant association in allele frequency distribution with CAD in both the Japanese (Odds ratio (OR)=1.63, 95% confidence interval (CI); 1.41-1.89, P=5.0 x 10(-11), corrected P (Pc)=4.0 x 10(-10)) and Korean populations (OR=1.68, 95% CI; 1.41-2.00, P=6.5 x 10(-9), Pc=5.2 x 10(-9)), and a meta-analysis showed a significant association in the East Asian populations (OR=1.65, 95% CI; 1.48-1.85, P=1.8 x 10(-18), Pc=1.4 x 10(-17)), whereas no evidence of association was found for the other SNPs. In addition, a combined analysis of BRAP and another CAD locus on 9p21 suggested that these loci had a synergistic role in the susceptibility. Failure to replicate the association with the other SNPs, which were reported in the European populations, suggested that their contributions to CAD were not large enough to be readily captured in the East Asian populations. Journal of Human Genetics (2009) 54, 642-646; doi:10.1038/jhg.2009.87; published online 28 August 2009

    DOI: 10.1038/jhg.2009.87

    Web of Science

    PubMed

  20. Impact of novel TRIM5 alpha variants, Gly110Arg and G176del, on the anti-HIV-1 activity and the susceptibility to HIV-1 infection 査読有り

    Toshiaki Nakajima, Emi E. Nakayama, Gurvinder Kaur, Hiroshi Terunuma, Jun-ich Mimaya, Hitoshi Ohtani, Narinder Mehra, Tatsuo Shiod, Akinori Kimura

    AIDS   23 巻 ( 16 ) 頁: 2091 - 2100   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objective: TRIM5 alpha is one of the factors contributing to intracellular defense mechanisms against HIV-1 infection. We investigated the association of TRIM5 alpha sequence variations with the susceptibility to HIV-1 infection in Japanese and Indian.
    Design: Sequence variations in TRIM5 alpha were investigated in HIV-1-infected patients and ethnic-matched controls. Functional alterations caused by rare variants were analyzed.
    Methods: We sequenced TRIM5 alpha-exon 2 in both Japanese (94 HIV-1-infected patients and 487 controls) and Indian (101 HIV-1-infected patients and 99 controls). Frequency of variants and haplotypes were compared between the HIV-1-infected patients and controls. Functional analyses were performed for two rare variants, Gly110Arg and G176del.
    Results: The frequency of 43Tyr-allele in the Indian HIV-1-infected patients was significantly lower than that in the ethnic-matched controls (odds ratio=0.52, 95% confidence interval = 0.31-0.89, P=0.015). A similar tendency was observed in Japanese sample, although it was not statistically significant (odds ratio = 0.67, 95% confidence interval = 0.43-1.05, P=0.095). On the other hand, haplotype analyses revealed that the haplotype carrying the 43Tyr-allele was significantly associated with the reduced susceptibility to HIV-1 infection in both ethnic groups. Functional analysis revealed that Gly110Arg variant weakened the anti-HIV-1 and anti-HIV-2 activities of human TRIM5a, whereas the truncated G176del-TRIM5 enhanced the antiviral activity of coexpressed TRIM5a. Epidemiological data were consistent in that Gly110Arg and G176del were associated with the susceptibility to and protection from HIV-1 infection, respectively.
    Conclusion: Both common and rare variants of TRIM5a are associated with the susceptibility to HIV-1 infection. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

    DOI: 10.1097/QAD.0b013e328331567a

    Web of Science

    PubMed

  21. Natural selection in the TLR-related genes in the course of primate evolution 査読有り

    Toshiaki Nakajima, Hitoshi Ohtani, Yoko Satta, Yasuhiro Uno, Hirofumi Akari, Takafumi Ishida, Akinori Kimura

    IMMUNOGENETICS   60 巻 ( 12 ) 頁: 727 - 735   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    The innate immune system constitutes the front line of host defense against pathogens. Toll-like receptors (TLRs) recognize molecules derived from pathogens and play crucial roles in the innate immune system. Here, we provide evidence that the TLR-related genes have come under natural selection pressure in the course of primate evolution. We compared the nucleotide sequences of 16 TLR-related genes, including TLRs (TLR1-10), MYD88, TILAP, TICAM1, TICAM2, MD2, and CD14, among seven primate species. Analysis of the non-synonymous/synonymous substitution ratio revealed the presence of both strictly conserved and rapidly evolving regions in the TLR-related genes. The genomic segments encoding the intracellular Toll/interleukin 1 receptor domains, which exhibited lower rates of non-synonymous substitution, have undergone purifying selection. In contrast, TLR4, which carried a high proportion of non-synonymous substitutions in the part of extracellular domain spanning 200 amino acids, was found to have been the suggestive target of positive Darwinian selection in primate evolution. However, sequence analyses from 25 primate species, including eight hominoids, six Old World monkeys, eight New World monkeys, and three prosimians, showed no evidence that the pressure of positive Darwinian selection has shaped the pattern of sequence variations in TLR4 among New World monkeys and prosimians.

    DOI: 10.1007/s00251-008-0332-0

    Web of Science

    PubMed

  22. Copy number variations of CCL3L1 and long-term prognosis of HIV-1 infection in asymptomatic HIV-infected Japanese with hemophilia 査読有り

    Toshiaki Nakajima, Hitoshi Ohtani, Taeko Naruse, Hiroki Shibata, Jun-ich Mimaya, Hiroshi Terunuma, Akinori Kimura

    IMMUNOGENETICS   59 巻 ( 10 ) 頁: 793 - 798   2007年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    We set up a cohort of HIV-infected, asymptomatic Japanese patients with hemophilia for follow-up study in 1995. All subjects who had been infected with HIV-1 for more than 10 years met the criteria for long-term non-progressors (LTNPs) at the time of entry; however, some of them later developed lymphopenia and required antiretroviral treatment during five more years of observation. In this study, we investigated the impacts of the CCL3L1 dose on the long-term prognosis in the subjects with chronic HIV-1 infection. We collected genomic DNA from 95 long-term survivors including 48 nonprogressors and 47 subjects receiving antiretroviral treatment. The distributions of CCL3L1 copy number significantly differed between the 95 HIV-1-infected subjects with hemophilia and 205 controls. Average copy number of CCL3L1 in the HIV-1-infected subjects was significantly lower than in control (5.00 +/- 0.22 vs 3.35 +/- 0.24, p &lt; 0.001). Moreover, the subjects possessing two or less copies of CCL3L1 had significantly higher risk of acquiring HIV-1. However, CCL3L1 copy number variations had no significant effect on the disease progression among the LTNP subjects who had been afflicted with chronic HIV-1 infection for more than 15 years, when compared between nonprogressors and patients under treatment (3.68 +/- 0.37 vs 3.02 +/- 0.29, ns). Furthermore, variations in the CCL3L1 copy number had little effect on the levels of HIV-1 load among them. We conclude that variation in the CCL3L1 copy number is apparently not a factor that determines the prognosis of chronic HIV-1 infection, even though it is linked to HIV-1 susceptibility.

    DOI: 10.1007/s00251-007-0252-4

    Web of Science

    PubMed

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書籍等出版物 1

  1. 実験医学増刊 エピゲノム研究

    大谷仁志( 担当: 分担執筆 ,  範囲: DNAメチル化状態に基づいた新たな膀胱がん診断マーカー)

    羊土社  2016年 

講演・口頭発表等 6

  1. レトロトランスポゾンの活性化が抗がん剤の作用機序の一端を担う 招待有り

    大谷仁志

    第92回日本遺伝学会大会  2020年9月 

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    記述言語:日本語   会議種別:口頭発表(招待・特別)  

  2. 内在性レトロウイルス群はその進化的年齢ごとに異なったエピジェネティック制御を受ける 招待有り

    大谷仁志

    公開セミナー(慶應義塾大学)  2020年3月 

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    記述言語:日本語   会議種別:公開講演,セミナー,チュートリアル,講習,講義等  

  3. 宿主自然免疫システム活性化における内在性レトロウイルスの潜在的機能 招待有り

    大谷仁志

    公開セミナー(東京大学)  2019年7月 

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    記述言語:日本語   会議種別:公開講演,セミナー,チュートリアル,講習,講義等  

  4. A switch in epigenetic silencing mechanisms of endogenous retroviruses during human genome evolution 国際会議

    大谷仁志

    AACR Annual Meeting  2018年4月 

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    記述言語:英語   会議種別:口頭発表(一般)  

  5. DmGTSF1 is a component of the Piwi–piRNA-mediated transcriptional transposon silencing machinery in Drosophila 招待有り

    大谷仁志

    Seminar  2014年1月 

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    記述言語:英語   会議種別:公開講演,セミナー,チュートリアル,講習,講義等  

  6. DmGTSF1 is compenent for Piwi-piRISC -mediated transcriptional transposon silencing machinery in Drosophila ovarian somatic cells

    大谷仁志

    RNA Frontier Meeting  2013年9月 

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    記述言語:英語   会議種別:口頭発表(一般)  

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科研費 5

  1. 転移因子の発現誘導がもたらすI型インターフェロン 経路活性化を利用した新規がん治療法の基盤開発

    2021年1月 - 2023年3月

    加藤記念バイオサイエンス振興財団  加藤記念研究助成 

    大谷仁志

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    担当区分:研究代表者 

    配分額:2000000円 ( 直接経費:2000000円 )

  2. 転移因子特異的な脱メチル化系を用いた新規がん治療法の基盤開発

    2020年12月 - 2021年11月

    公益財団法人 鈴木謙三記念医科学応用研究財団  令和 2 年 度調査研究助成 

    大谷仁志

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    担当区分:研究代表者 

    配分額:1000000円 ( 直接経費:1000000円 )

  3. CRISPR/dCas9-TET1系を用いた転移因子のがん細胞における機能の解明

    研究課題/研究課題番号:20K22808  2020年9月 - 2022年3月

    日本学術振興会  科学研究費助成事業 研究活動スタート支援  研究活動スタート支援

    大谷 仁志

  4. CRISPR/dCas9-TET1 システムを用いた転移因子のがん細胞増殖抑制に対する潜在的機能 の解明

    2020年8月 - 2021年3月

    公益財団法人愛知県がん研究振興会  第45回がんその他の悪性新生物研究助成金 

    大谷仁志

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    担当区分:研究代表者 

    配分額:250000円 ( 直接経費:250000円 )

  5. 新たな核内レトロトランスポゾン抑制因子の同定

    2013年 - 2014年

    日本学術振興会  科学研究費助成事業 若手研究(B) 

    大谷仁志

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    担当区分:研究代表者  資金種別:競争的資金