Updated on 2022/04/13

写真a

 
OHTANI Hitoshi
 
Organization
Graduate School of Bioagricultural Sciences Department of Animal Sciences Assistant Professor
Graduate School
Graduate School of Bioagricultural Sciences
Undergraduate School
School of Agricultural Sciences Department of Bioresource Sciences
Title
Assistant Professor

Degree 1

  1. 博士(理学) ( 2011.3   東京医科歯科大学 ) 

Research Interests 6

  1. Non-coding RNA

  2. Genome evolution

  3. Epigenome

  4. Endogenous retrovirus

  5. Cancer therapy

  6. Bioinformatics

Research Areas 1

  1. Life Science / Genome biology

Research History 3

  1. 名古屋大学大学院   生命農学研究科動物科学専攻

    2020.4

  2. Van Andel Research Institute   Center of Epigenetics   PostDoc

    2014.5 - 2020.3

  3. Keio University   School of Medicine

    2011.4 - 2014.5

Education 1

  1. Tokyo Medical and Dental University   Biomedical Science PhD Program

    2005.4 - 2011.3

Awards 2

  1. AACR Annual Meeting Scholar-in-Training Award

    2018.4   AACR  

    Hitoshi Ohtani

  2. Academic awards of Japanese Society for Histocompatibility and Immunogenetics

    2006.9   Japanese Society for Histocompatibility and Immunogenetics  

    Hitoshi Ohtani

 

Papers 23

  1. Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity are Linked to Clinical Responses to 5-Azacytidine. Reviewed International journal

    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     2020.4

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    Language:English  

    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. Reviewed

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

    Genome research   Vol. 28 ( 8 ) page: 1147 - 1157   2018.8

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  3. Vitamin C increases viral mimicry induced by 5-aza-2 '-deoxycytidine Reviewed

    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   Vol. 113 ( 37 ) page: 10238 - 10244   2016.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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

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    PubMed

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

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

    GENES & DEVELOPMENT   Vol. 27 ( 15 ) page: 1656 - 1661   2013.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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

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  5. Dual EZH2 and G9a inhibition suppresses multiple myeloma cell proliferation by regulating the interferon signal and IRF4-MYC axis Reviewed International journal

    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   Vol. 7 ( 1 ) page: 7 - 7   2021.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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

    PubMed

    Other Link: http://www.nature.com/articles/s41420-020-00400-0

  6. Rewiring of chromatin state and gene expression by transposable elements

    Hitoshi Ohtani, Yuka W. Iwasaki

    Development, Growth & Differentiation     2021.5

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    Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1111/dgd.12735

  7. Rewiring of chromatin state and gene expression by transposable elements Invited Reviewed

    Hitoshi Ohtani, Yuka W. Iwasaki

        2021.4

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    Authorship:Lead author, Corresponding author  

  8. Armitage determines Piwi-piRISC processing from precursor formation and quality control to inter-organelle translocation. Reviewed International journal

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

    EMBO reports   Vol. 21 ( 2 ) page: e48769   2020.2

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    Language:English   Publishing type:Research paper (scientific journal)  

    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

  9. Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes. Reviewed International journal

    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   Vol. 11 ( 1 ) page: 143 - 143   2019.10

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    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

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  10. Epigenetic therapy in immune-oncology. Reviewed

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

    Nature reviews. Cancer   Vol. 19 ( 3 ) page: 151 - 161   2019.3

  11. Integrative Epigenetic Analysis Reveals Therapeutic Targets to the DNA Methyltransferase Inhibitor Guadecitabine (SGI-110) in Hepatocellular Carcinoma. Reviewed

    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.)   Vol. 68 ( 4 ) page: 1412 - 1428   2018.10

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  12. Dual Inhibition of DNA and Histone Methyltransferases Increases Viral Mimicry in Ovarian Cancer Cells. Reviewed

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

    Cancer research   Vol. 78 ( 20 ) page: 5754 - 5766   2018.10

  13. APOBEC3H polymorphisms and susceptibility to HIV-1 infection in an Indian population Reviewed

    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   Vol. 61 ( 3 ) page: 263 - 265   2016.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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

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  14. APOBEC3H polymorphisms associated with the susceptibility to HIV-1 infection and AIDS progression in Japanese Reviewed

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

    IMMUNOGENETICS   Vol. 67 ( 4 ) page: 253 - 257   2015.4

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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

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  15. Status of TIM-1 exon 4 haplotypes and CD4+T cell counts in HIV-1 seroprevalent North Indians Reviewed

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

    HUMAN IMMUNOLOGY   Vol. 74 ( 2 ) page: 163 - 165   2013.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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

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  16. Lineage-specific evolution of T-cell immunoglobulin and mucin domain 1 gene in the primates Reviewed

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

    IMMUNOGENETICS   Vol. 64 ( 9 ) page: 669 - 678   2012.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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

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  17. Molecular evolution of immunoglobulin superfamily genes in primates Reviewed

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

    IMMUNOGENETICS   Vol. 63 ( 7 ) page: 417 - 428   2011.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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

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  18. No Evidence of an Association between the APOBEC3B Deletion Polymorphism and Susceptibility to HIV Infection and AIDS in Japanese and Indian Populations Reviewed

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

    JOURNAL OF INFECTIOUS DISEASES   Vol. 202 ( 5 ) page: 815 - U166   2010.9

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    Language:English   Publisher:OXFORD UNIV PRESS INC  

    DOI: 10.1086/655227

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  19. TIM1 haplotype may control the disease progression to AIDS in a HIV-1-infected female cohort in Thailand Reviewed

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

    AIDS   Vol. 24 ( 11 ) page: 1625 - 1631   2010.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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

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  20. Validation of eight genetic risk factors in East Asian populations replicated the association of BRAP with coronary artery disease Reviewed

    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   Vol. 54 ( 11 ) page: 642 - 646   2009.11

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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

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  21. Impact of novel TRIM5 alpha variants, Gly110Arg and G176del, on the anti-HIV-1 activity and the susceptibility to HIV-1 infection Reviewed

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

    AIDS   Vol. 23 ( 16 ) page: 2091 - 2100   2009.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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

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  22. Natural selection in the TLR-related genes in the course of primate evolution Reviewed

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

    IMMUNOGENETICS   Vol. 60 ( 12 ) page: 727 - 735   2008.12

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    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

  23. Copy number variations of CCL3L1 and long-term prognosis of HIV-1 infection in asymptomatic HIV-infected Japanese with hemophilia Reviewed

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

    IMMUNOGENETICS   Vol. 59 ( 10 ) page: 793 - 798   2007.10

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    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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Books 1

  1. 実験医学増刊 エピゲノム研究

    大谷仁志( Role: Contributor ,  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 

Presentations 8

  1. A switch in epigenetic silencing mechanisms of endogenous retroviruses during human genome evolution International conference

    Hitoshi Ohtani

    AACR Annual Meeting  2018.4 

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    Language:English   Presentation type:Oral presentation (general)  

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

    Hitoshi Ohtani

    RNA Frontier Meeting  2013.9 

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    Language:English   Presentation type:Oral presentation (general)  

  3. DmGTSF1 is a component of the Piwi–piRNA-mediated transcriptional transposon silencing machinery in Drosophila Invited

    Hitoshi Ohtani

    Seminar  2014.1 

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    Language:English   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

  4. 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 Invited

    大谷仁志

    第92回日本遺伝学会大会  2020.9 

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    Language:Japanese   Presentation type:Oral presentation (invited, special)  

  5. 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 Invited

    大谷仁志

    公開セミナー(東京大学)  2019.7 

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    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

  6. 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 Invited

    大谷仁志

    公開セミナー(慶應義塾大学)  2020.3 

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    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

  7. 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 Invited

    大谷仁志

    第92回日本遺伝学会大会  2020.9.1 

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    Language:Japanese   Presentation type:Oral presentation (invited, special)  

  8. レトロトランスポゾンのDNA 脱メチル化が癌細胞の増殖を抑制する Invited

    大谷仁志

    第93回日本遺伝学会大会  2021.9.1 

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KAKENHI (Grants-in-Aid for Scientific Research) 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

    2021.1 - 2023.3

    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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    Authorship:Principal investigator 

    Grant amount:\2000000 ( Direct Cost: \2000000 )

  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

    2020.12 - 2021.11

    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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    Authorship:Principal investigator 

    Grant amount:\1000000 ( Direct Cost: \1000000 )

  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

    Grant number:20K22808  2020.9 - 2022.3

    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

    2020.8 - 2021.3

    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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    Authorship:Principal investigator 

    Grant amount:\250000 ( Direct Cost: \250000 )

  5. 新たな核内レトロトランスポゾン抑制因子の同定

    2013 - 2014

    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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    Authorship:Principal investigator  Grant type:Competitive