Updated on 2026/07/20

All information, except for affiliations, is reprinted from the information registered on researchmap.

写真a

 
Takayuki Nojima
 
Organization
Graduate School of Medicine Department of Medicine Biochemistry Professor
School of Medicine Medical Course
Title
Professor
Homepage
https://pol2-nascentrna.net/
External link

Research Interests

  • Transcription termination

  • Cancer genome

  • Oxford Nanoproe Technologies

  • Splicing inhibitors

  • RNA degradation

  • Herpes Simplex Virus

  • Long noncoding RNA

  • RNA cleavage

  • Influenza virus

  • Transcription

  • DNA damage

  • cellular senescence

  • R loops

  • RNA polymerase II CTD

  • Nascent RNA

  • mammmalian NET-seq

  • RNA processing

  • Cancer gene mutations

  • Premature termination

Research Areas

  • Life Science / Genome biology  / Tanscriptomics, Epigenetics, Camparative genome transcription, Intergenic region、Transcription start site、Transcription end site, Co-transcriptional RNA cleavage, RNA degaradation

  • Life Science / Molecular biology  / Transcription, RNA, DNA damage, Cancer, Virus infection

Education

  • Tokyo Medical and Dental University   Biomedical Science PhD Program

    2004.4 - 2006.3

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  • Kitasato University   Graduate School of Pharmaceutical Sciences

    2001.4 - 2003.3

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  • Kitasato University   School of Pharmaceutical Sciences

    1997.4 - 2001.3

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    Country： Japan

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Research History

  • Yokohama City University   Graduate school of Medicine   Professor

    2026.4

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    Country：Japan

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  • Yokohama City University   Department of Medicine   Professor

    2026.4

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    Country：Japan

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  • Kyushu University   Medical Institute of Bioregulation   Associate Professor（PI）

    2021.2 - 2026.3

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    Country：Japan

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  • University of Oxford   Sir William Dunn School of Pathology   Senior research fellow

    2014.10 - 2021.1

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  • University of Oxford   Sir William Dunn School of Pathology   Post doc

    2010.9 - 2014.9

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  • Tokyo Medical and Dental University

    2006.4 - 2010.8

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Professional Memberships

Papers

  • PUF60 is a Critical Regulator of PKM Splicing During Myogenesis. Reviewed International journal

    So Masaki, Takayuki Nojima, Takako Oshiro-Ideue, Asami Suenaga, Akihide Takeuchi, Isao Kii, Kenji Suzuki, Satoshi Tanaka, Masatoshi Hagiwara, Naoyuki Kataoka

    Molecular and cellular biology   1 - 16   2026.7

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    Pyruvate kinase M (PKM) catalyzes the conversion of phosphoenolpyruvate to pyruvate in glycolysis and exists as two splice isoforms, PKM1 and PKM2, generated from alternative splicing of mutually exclusive exons 9 or 10, respectively. The expression balance between PKM1 and PKM2 is tightly regulated in a cell-type-specific manner. PKM1 is predominantly expressed in tissues such as skeletal muscle, heart, and brain, whereas PKM2 is prevalent in most other tissues and various cancer cells. Despite its importance, the trans-acting factors promoting exon 9 selection in a tissue-specific context remain largely unknown. Here, using a multi-color splicing reporter system for cell-based cDNA screening, we identified PUF60 as a novel trans-acting factor that promotes PKM1-type splicing. We also demonstrated that PUF60 induction and the resulting splicing switch are essential for myotube formation during C2C12 differentiation. This study establishes PUF60 as a critical regulator of muscle-specific splicing and provides new insights into the fundamental mechanisms governing skeletal muscle differentiation.

    DOI： 10.1080/10985549.2026.2699151

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  • SETD2 methyltransferase activity promotes correct transcription initiation and termination Reviewed International journal

    Magda Kopczyńska, Chihiro Nakayama, Agata Stępień, Shoko Ito, Koshi Imami, Michał R Gdula, Takayuki Nojima, Kinga Kamieniarz-Gdula

    EMBO Reports   2026.3

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    Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    SETD2 is a methyltransferase responsible for depositing histone H3 lysine 36 trimethylation (H3K36me3). Loss of its enzymatic activity occurs in some cancers, including renal cell carcinoma. SETD2 mutations have been linked to delayed transcription termination but have not been explored in depth. Here, using nascent transcriptomics in SETD2 knockout and patient-derived cells, we reveal a dichotomy in SETD2 functions depending on the affected protein-coding gene. The majority of genes, named class I, are dependent on SETD2 function for transcription initiation, yet terminate transcription in the usual locations. In contrast, for class II genes, corresponding to 15-25% of active protein-coding genes, transcription initiation is robust in absence of SETD2 activity; however, widespread transcriptional readthrough occurs. Defective termination following SETD2 loss/mutation is associated with increased cryptic transcription initiation and impaired 3' pre-mRNA cleavage. Additionally, alternative polyadenylation upon SETD2 activity loss is highly cell type specific, and no relationship with transcription readthrough was observed. We demonstrate that methyltransferase activity of SETD2 stimulates proper initiation, prevents cryptic initiation and promotes efficient 3' end processing, however, it does so indirectly.

    DOI： 10.1038/s44319-026-00744-1

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  • NELF prevents transcriptional readthrough into DNA replication zones in cancer cells. Reviewed International journal

    Chihiro Nakayama, Qi Fang, Yasukazu Daigaku, Yuki Aoi, Shoko Ito, Mami Takahashi, Reo Shimatani, Tamiko Minamisawa, Yagiz Ozturk, Hiroshi Kimura, Ali Shilatifard, Michael Tellier, Takayuki Nojima

    EMBO reports   2026.2

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Regulation of RNA polymerase II (Pol II) transcription is closely associated with cell proliferation. However, it remains unclear how the Pol II transcription program is rewired in cancer to promote uncontrolled growth. Here, we find that expression of NELFCD, a known negative transcription elongation factor, is upregulated in colorectal tumors. Auxin-dependent protein degradation of NELF-C in combination with nascent transcript sequencing demonstrates a direct role of NELF-C on Pol II transcription in this cancer. Strikingly, we demonstrate that the acute loss of NELF-C protein globally redistributes termination factors and perturbs Pol II transcription termination. These changes drive pervasive Pol II transcription into DNA replication zones, leading to transcription-replication conflict that may block the cell cycle in G1 or early S phase. Our findings reveal a previously unrecognized role of NELF in transcription termination and highlight NELF as a potential therapeutic target in colorectal cancer.

    DOI： 10.1038/s44319-026-00700-z

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  • DNA-directed termination of mammalian RNA polymerase II Reviewed International journal

    Lee Davidson, Jérôme O Rouvière, Rui Sousa-Luís, Takayuki Nojima, Nicholas Proudfoot, Torben Heick Jensen, Steven West

    Genes and Development   38 ( 21-24 )   998 - 1019   2024.11

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

    <jats:title>ABSTRACT</jats:title><jats:p>The best-studied mechanism of eukaryotic RNA polymerase II (RNAPII) transcriptional termination involves polyadenylation site-directed cleavage of the nascent RNA. The RNAPII-associated cleavage product is then degraded by XRN2, dislodging RNAPII from the DNA template. In contrast, prokaryotic RNAP and eukaryotic RNAPIII often terminate directly at T-tracts in the coding DNA strand. Here, we demonstrate a similar and omnipresent capability for mammalian RNAPII. XRN2- and T-tract-dependent termination are independent - the latter usually acting when XRN2 cannot be engaged. We show that T-tracts terminate snRNA transcription, previously thought to require the Integrator complex. Importantly, we find genome-wide termination at T-tracts in promoter-proximal regions, but not within protein-coding gene bodies. XRN2-dependent termination dominates downstream of protein-coding genes, but the T-tract process is sometimes employed. Overall, we demonstrate global DNA-directed attrition of RNAPII transcription, suggesting that RNAPs retain the potential to terminate over T-rich sequences throughout evolution.</jats:p>

    DOI： 10.1101/2024.06.01.596947

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  • NELF coordinates Pol II transcription termination and DNA replication initiation

    Chihiro Nakayama, Yasukazu Daigaku, Yuki Aoi, Qi Fang, Hiroshi Kimura, Ali Shilatifard, Michael Tellier, Takayuki Nojima

    2024.2

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cold Spring Harbor Laboratory  

    SUMMARY

    Regulation of RNA polymerase II (Pol II) transcription is closely associated with cell proliferation. However, it remains unclear how the Pol II transcription program is altered in cancer to favour cell growth. Here, we find that gene expression ofNELFCD, a known negative elongation factor, is up-regulated in colorectal tumours. To dissect the direct role of NELF-C on Pol II transcription in such cancer, we employed an auxin-dependent protein degradation system for NELF-C in combination with nascent transcript sequencing technologies. Strikingly, we demonstrated that the acute loss of NELF-C protein globally perturbs Pol II transcription termination and also increases transcription elongation rate, independently of promoter-proximal Pol II pausing. This results in Pol II transcription into DNA replication initiation zones, and may link to failure of the cell cycle transition into S phase. We anticipate that NELF will be a potential therapeutic target to restrict colorectal cancers by promoting transcription-replication conflict.

    HIGHLIGHTS

    Expression ofNELFCDtranscript is up-regulated in colorectal tumors

    NELF-C protein is mandatory for the transition between G1-S phases during cell cycle

    NELF-C loss impairs transcription termination independently of Pol II promoter-proximal pausing

    NELF-C loss leads Pol II to invade DNA replication initiation zones

    DOI： 10.1101/2024.01.31.578294

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  • PTBP1-activated co-transcriptional splicing controls epigenetic status of pluripotent stem cells Reviewed

    Camilla Iannone, Yaroslav Kainov, Anna Zhuravskaya, Fursham Hamid, Takayuki Nojima, Eugene V. Makeyev

    Molecular Cell   2023.1

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    Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.molcel.2022.12.014

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  • CDK9 and PP2A regulate RNA polymerase II transcription termination and coupled RNA maturation. Reviewed International journal

    Michael Tellier, Justyna Zaborowska, Jonathan Neve, Takayuki Nojima, Svenja Hester, Marjorie Fournier, Andre Furger, Shona Murphy

    EMBO reports   23 ( 10 )   e54520   2022.10

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

    CDK9 is a kinase critical for the productive transcription of protein-coding genes by RNA polymerase II (pol II). As part of P-TEFb, CDK9 phosphorylates the carboxyl-terminal domain (CTD) of pol II and elongation factors, which allows pol II to elongate past the early elongation checkpoint (EEC) encountered soon after initiation. We show that, in addition to halting pol II at the EEC, loss of CDK9 activity causes premature termination of transcription across the last exon, loss of polyadenylation factors from chromatin, and loss of polyadenylation of nascent transcripts. Inhibition of the phosphatase PP2A abrogates the premature termination and loss of polyadenylation caused by CDK9 inhibition, indicating that this kinase/phosphatase pair regulates transcription elongation and RNA processing at the end of protein-coding genes. We also confirm the splicing factor SF3B1 as a target of CDK9 and show that SF3B1 in complex with polyadenylation factors is lost from chromatin after CDK9 inhibition. These results emphasize the important roles that CDK9 plays in coupling transcription elongation and termination to RNA maturation downstream of the EEC.

    DOI： 10.15252/embr.202154520

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  • Mechanisms of lncRNA biogenesis as revealed by nascent transcriptomics Invited Reviewed

    Takayuki Nojima, Nick J. Proudfoot

    Nature Reviews Molecular Cell Biology   2022.6

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    DOI： 10.1038/s41580-021-00447-6

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    Other Link： https://www.nature.com/articles/s41580-021-00447-6

  • POINT technology illuminates the processing of polymerase-associated intact nascent transcripts. Reviewed International journal

    Rui Sousa-Luís, Gwendal Dujardin, Inna Zukher, Hiroshi Kimura, Carika Weldon, Maria Carmo-Fonseca, Nick J Proudfoot, Takayuki Nojima

    Molecular cell   2021.5

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    Authorship：Lead author,　Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Mammalian chromatin is the site of both RNA polymerase II (Pol II) transcription and coupled RNA processing. However, molecular details of such co-transcriptional mechanisms remain obscure, partly because of technical limitations in purifying authentic nascent transcripts. We present a new approach to characterize nascent RNA, called polymerase intact nascent transcript (POINT) technology. This three-pronged methodology maps nascent RNA 5' ends (POINT-5), establishes the kinetics of co-transcriptional splicing patterns (POINT-nano), and profiles whole transcription units (POINT-seq). In particular, we show by depletion of the nuclear exonuclease Xrn2 that this activity acts selectively on cleaved 5' P-RNA at polyadenylation sites. Furthermore, POINT-nano reveals that co-transcriptional splicing either occurs immediately after splice site transcription or is delayed until Pol II transcribes downstream sequences. Finally, we connect RNA cleavage and splicing with either premature or full-length transcript termination. We anticipate that POINT technology will afford full dissection of the complexity of co-transcriptional RNA processing.

    DOI： 10.1016/j.molcel.2021.02.034

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  • Enhancers predominantly regulate gene expression during differentiation via transcription initiation. Reviewed International journal

    Martin S C Larke, Ron Schwessinger, Takayuki Nojima, Jelena Telenius, Robert A Beagrie, Damien J Downes, A Marieke Oudelaar, Julia Truch, Bryony Graham, M A Bender, Nicholas J Proudfoot, Douglas R Higgs, Jim R Hughes

    Molecular cell   2021.1

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    Gene transcription occurs via a cycle of linked events, including initiation, promoter-proximal pausing, and elongation of RNA polymerase II (Pol II). A key question is how transcriptional enhancers influence these events to control gene expression. Here, we present an approach that evaluates the level and change in promoter-proximal transcription (initiation and pausing) in the context of differential gene expression, genome-wide. This combinatorial approach shows that in primary cells, control of gene expression during differentiation is achieved predominantly via changes in transcription initiation rather than via release of Pol II pausing. Using genetically engineered mouse models, deleted for functionally validated enhancers of the α- and β-globin loci, we confirm that these elements regulate Pol II recruitment and/or initiation to modulate gene expression. Together, our data show that gene expression during differentiation is regulated predominantly at the level of initiation and that enhancers are key effectors of this process.

    DOI： 10.1016/j.molcel.2021.01.002

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  • CDK12 globally stimulates RNA polymerase II transcription elongation and carboxyl-terminal domain phosphorylation Reviewed

    Tellier, M., Zaborowska, J., Caizzi, L., Mohammad, E., Velychko, T., Schwalb, B., Ferrer-Vicens, I., Blears, D., Nojima, T., Cramer, P., Murphy, S.

    Nucleic Acids Research   48 ( 14 )   2020.6

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    Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

    DOI： 10.1093/nar/gkaa514

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  • SCAF4 and SCAF8, mRNA Anti-Terminator Proteins Reviewed

    Gregersen, L.H., Mitter, R., Ugalde, A.P., Nojima, T., Proudfoot, N.J., Agami, R., Stewart, A., Svejstrup, J.Q.

    Cell   177 ( 7 )   2019.5

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    DOI： 10.1016/j.cell.2019.04.038

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  • Selective Roles of Vertebrate PCF11 in Premature and Full-Length Transcript Termination Reviewed

    Kamieniarz-Gdula, K., Gdula, M.R., Panser, K., Nojima, T., Monks, J., Wi?niewski, J.R., Riepsaame, J., Brockdorff, N., Pauli, A., Proudfoot, N.J.

    Molecular Cell   74 ( 1 )   158 - 172.e9   2019.4

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    Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.molcel.2019.01.027

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  • Deregulated Expression of Mammalian lncRNA through Loss of SPT6 Induces R-Loop Formation, Replication Stress, and Cellular Senescence Reviewed

    Nojima, T., Tellier, M., Foxwell, J., Ribeiro de Almeida, C., Tan-Wong, S.M., Dhir, S., Dujardin, G., Dhir, A., Murphy, S., Proudfoot, N.J.

    Molecular Cell   72 ( 6 )   2018.11

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    DOI： 10.1016/j.molcel.2018.10.011

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  • RNA Polymerase II Phosphorylated on CTD Serine 5 Interacts with the Spliceosome during Co-transcriptional Splicing Reviewed

    Nojima, T., Rebelo, K., Gomes, T., Grosso, A.R., Proudfoot, N.J., Carmo-Fonseca, M.

    Molecular Cell   72 ( 2 )   369 - 379.e4   2018.10

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    Authorship：Lead author   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.molcel.2018.09.004

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  • Mitochondrial double-stranded RNA triggers antiviral signalling in humans Reviewed

    Ashish Dhir, Somdutta Dhir, Lukasz S. Borowski, Laura Jimenez, Michael Teitell, Agnès Rötig, Yanick J. Crow, Gillian I. Rice, Darragh Duffy, Christelle Tamby, Takayuki Nojima, Arnold Munnich, Manuel Schiff, Claudia Ribeiro de Almeida, Jan Rehwinkel, Andrzej Dziembowski, Roman J. Szczesny, Nicholas J. Proudfoot

    Nature   560 ( 7717 )   238 - 242   2018.7

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    DOI： 10.1038/s41586-018-0363-0

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  • Influenza Virus Mounts a Two-Pronged Attack on Host RNA Polymerase II Transcription Reviewed

    Bauer, D.L.V., Tellier, M., Mart{\'i}nez-Alonso, M., Nojima, T., Proudfoot, N.J., Murphy, S., Fodor, E.

    Cell Reports   23 ( 7 )   2119 - 2129.e3   2018.5

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    Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.celrep.2018.04.047

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  • Distinctive Patterns of Transcription and RNA Processing for Human lincRNAs Reviewed

    Margarita Schlackow, Takayuki Nojima, Tomas Gomes, Ashish Dhir, Maria Carmo-Fonseca, Nick J. Proudfoot

    Molecular Cell   65 ( 1 )   25 - 38   2017.1

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.molcel.2016.11.029

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  • Mammalian NET-seq analysis defines nascent RNA profiles and associated RNA processing genome-wide Reviewed

    Takayuki Nojima, Tomas Gomes, Maria Carmo-Fonseca, Nicholas J. Proudfoot

    Nature Protocols   11 ( 3 )   413 - 428   2016.3

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/nprot.2016.012

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  • Mammalian NET-Seq Reveals Genome-wide Nascent Transcription Coupled to RNA Processing Reviewed

    Takayuki Nojima, Tomas Gomes, Ana Rita Fialho Grosso, Hiroshi Kimura, Michael J. Dye, Somdutta Dhir, Maria Carmo-Fonseca, Nicholas J. Proudfoot

    Cell   161 ( 3 )   526 - 540   2015.4

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.cell.2015.03.027

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  • Definition of RNA Polymerase II CoTC Terminator Elements in the Human Genome Reviewed

    Takayuki Nojima, Martin Dienstbier, Shona Murphy, Nicholas J. Proudfoot, Michael J. Dye

    Cell Reports   3 ( 4 )   1080 - 1092   2013.4

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.celrep.2013.03.012

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  • Herpesvirus protein ICP27 switches PML isoform by altering mRNA splicing Reviewed

    Takayuki Nojima, Takako Oshiro-Ideue, Hiroto Nakanoya, Hidenobu Kawamura, Tomomi Morimoto, Yasushi Kawaguchi, Naoyuki Kataoka, Masatoshi Hagiwara

    Nucleic Acid Research   37 ( 19 )   6515 - 6527   2009.10

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1093/nar/gkp633

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  • Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA Reviewed

    Daisuke Kaida, Hajime Motoyoshi, Etsu Tashiro, Takayuki Nojima, Masatoshi Hagiwara, Ken Ishigami, Hidenori Watanabe, Takeshi Kitahara, Tatsuhiko Yoshida, Hidenori Nakajima, Tokio Tani, Sueharu Horinouchi, Minoru Yoshida

    NATURE CHEMICAL BIOLOGY   3 ( 9 )   576 - 583   2007.9

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

    DOI： 10.1038/nchembio.2007.18

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  • The interaction between cap-binding complex and RNA export factor is required for intronless mRNA export Reviewed

    Takayuki Nojima, Tetsuro Hirose, Hiroshi Kimura, Masatoshi Hagiwara

    JOURNAL OF BIOLOGICAL CHEMISTRY   282 ( 21 )   15645 - 15651   2007.5

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1074/jbc.M700629200

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  • eIF2D promotes 40S ribosomal subunit recycling during intrinsic ribosome destabilization. Reviewed International journal

    Kazuya Ichihara, Taichi Shiraishi, Yuhei Chadani, Yuki Kito, Chisa Shiraishi, Mina Hirata, Yuta Takahashi, Akinao Kobo, Atsushi Hatano, Masaki Matsumoto, Kodai Machida, Hiroaki Imataka, Atsushi Toyoda, Emi Mishiro-Sato, Takayuki Nojima, Takuhiro Ito, Hideki Taguchi, Keiichi I Nakayama, Akinobu Matsumoto

    Nucleic acids research   53 ( 22 )   2025.11

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    Although eukaryotic initiation factor 2D (eIF2D) is implicated in translation initiation, reinitiation, and ribosome recycling, its precise role remains unclear. Here, we show that eIF2D promotes 40S ribosome recycling during intrinsic ribosome destabilization (IRD), a process in which ribosomes stochastically destabilize while translating proteins with consecutive acidic amino acids at their NH2-terminus. Unrecycled 40S ribosomes accumulate in eIF2D-deficient cells, leading to 80S ribosome stalling. Selective translation complex profiling (TCP-seq) reveals that eIF2D preferentially associates with IRD-prone regions. The winged helix domain, unique to eIF2D but absent in MCTS1-DENR, enhances its binding to 40S subunits, but likely clashes with ABCE1 during stop-codon-associated recycling. Loss of eIF2D reduces the expression of IRD-inducing proteins, including splicing factors. Together, these findings define a previously unappreciated role for eIF2D in 40S recycling and clarify its mechanistic divergence from the MCTS1-DENR complex.

    DOI： 10.1093/nar/gkaf1322

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  • Single-molecule multimodal timing of in vivo mRNA synthesis

    A.J. Sethi, Marco Guarnacci, Muhammad Bilal, Karthik Subramanian Krishnan, Azusa Hayashi, Madhu Kanchi, Takayuki Nojima, Thomas Preiss, Eduardo Eyras, Rippei Hayashi

    BioRxiv   2025.4

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  • Defining gene ends: RNA polymerase II CTD threonine 4 phosphorylation marks transcription termination regions genome-wide. Reviewed International journal

    Magda Kopczyńska, Upasana Saha, Anastasiia Romanenko, Takayuki Nojima, Michał R Gdula, Kinga Kamieniarz-Gdula

    Nucleic acids research   53 ( 2 )   2025.1

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

    Defining the beginning of a eukaryotic protein-coding gene is relatively simple. It corresponds to the first ribonucleotide incorporated by RNA polymerase II (Pol II) into the nascent RNA molecule. This nucleotide is protected by capping and maintained in the mature messenger RNA (mRNA). However, in higher eukaryotes, the end of mRNA is separated from the sites of transcription termination by hundreds to thousands of base pairs. Currently used genomic annotations only take account of the end of the mature transcript - the sites where pre-mRNA cleavage occurs, while the regions in which transcription terminates are unannotated. Here, we describe the evidence for a marker of transcription termination, which could be widely applicable in genomic studies. Pol II termination regions can be determined genome-wide by detecting Pol II phosphorylated on threonine 4 of its C-terminal domain (Pol II CTD-T4ph). Pol II in this state pauses before leaving the DNA template. Up to date this potent mark has been underused because the evidence for its place and role in termination is scattered across multiple publications. We summarize the observations regarding Pol II CTD-T4ph in termination regions and present bioinformatic analyses that further support Pol II CTD-T4ph as a global termination mark in animals.

    DOI： 10.1093/nar/gkae1240

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  • Simultaneous studies of gene expression and alternative polyadenylation in primary human immune cells Reviewed International journal

    Joana Wilton, Michael Tellier, Takayuki Nojima, Angela M. Costa, Maria Jose Oliveira, Alexandra Moreira

    Methods in Enzymology   655   349 - 399   2021.1

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

    Transcription termination in eukaryotic cells involves the recognition of polyadenylation signals (PAS) that signal the site of pre-mRNA cleavage and polyadenylation. Most eukaryotic genes contain multiple PAS that are used by alternative polyadenylation (APA), a co-transcriptional process that increases transcriptomic diversity and modulates the fate of the mRNA and protein produced. However, current tools to pinpoint the relationship between mRNAs in different subcellular fractions and the gene expression outcome are lacking, particularly in primary human immune cells, which, due to their nature, are challenging to study. Here, we describe an integrative approach using subcellular fractionation and RNA isolation, chromatin-bound and nucleoplasmic RNA-Sequencing, 3' RNA-Sequencing and bioinformatics, to identify accurate APA mRNA isoforms and to quantify gene expression in primary human macrophages. Our protocol includes macrophage differentiation and polarization, co-culture with cancer cells, and gene silencing by siRNA. This method allows the simultaneous identification of macrophage APA mRNA isoforms integrated with the characterization of nuclear APA events, the identification of the molecular mechanisms involved, as well as the gene expression alterations caused by the cancer-macrophage crosstalk. With this methodology we identified macrophage APA mRNA signatures driven by the cancer cells that alter the macrophage inflammatory and transcriptomic profiles, with consequences for macrophage physiology and tumor evasion.

    DOI： 10.1016/bs.mie.2021.04.004

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  • RBM24 promotes U1 snRNP recognition of the mutated 5 ' splice site in the IKBKAP gene of familial dysautonomia Reviewed

    Kenji Ohe, Mayumi Yoshida, Akiko Nakano-Kobayashi, Motoyasu Hosokawa, Yukiya Sako, Maki Sakuma, Yukiko Okuno, Tomomi Usui, Kensuke Ninomiya, Takayuki Nojima, Naoyuki Kataoka, Masatoshi Hagiwara

    RNA   23 ( 9 )   1393 - 1403   2017.9

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    DOI： 10.1261/rna.059428.116

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  • Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia Reviewed

    Mayumi Yoshida, Naoyuki Kataoka, Kenjyo Miyauchi, Kenji Ohe, Kei Iida, Suguru Yoshida, Takayuki Nojima, Yukiko Okuno, Hiroshi Onogi, Tomomi Usui, Akihide Takeuchi, Takamitsu Hosoya, Tsutomu Suzuki, Masatoshi Hagiwaraa

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   112 ( 9 )   2764 - 2769   2015.3

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

    DOI： 10.1073/pnas.1415525112

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  • Single-Cell Detection of Splicing Events with Fluorescent Splicing Reporters Reviewed

    Hidehito Kuroyanagi, Akihide Takeuchi, Takayuki Nojima, Masatoshi Hagiwara

    Alternative pre-mRNA Splicing: Theory and Protocols   298 - 309   2012.2

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    Language：English   Publishing type：Part of collection (book)   Publisher：Wiley-VCH  

    DOI： 10.1002/9783527636778.ch28

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  • Splicing Reporter Mice Revealed the Evolutionally Conserved Switching Mechanism of Tissue-Specific Alternative Exon Selection Reviewed

    Akihide Takeuchi, Motoyasu Hosokawa, Takayuki Nojima, Masatoshi Hagiwara

    PLOS ONE   5 ( 6 )   e10946   2010.6

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

    DOI： 10.1371/journal.pone.0010946

    Web of Science

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  • Splicing reporter mice revealed the evolutionally conserved switching mechanism of tissue-specific alternative splicing. PLOS One 5, e10946

    Takeuchi A, Hosokawa M, Nojima T, Hagiwara M

    2010

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  • Cross-talks between transcription and post-transcriptional events within a 'mRNA factory' Reviewed

    Masatoshi Hagiwara, Takayuki Nojima

    JOURNAL OF BIOCHEMISTRY   142 ( 1 )   11 - 15   2007.7

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    Authorship：Lead author   Language：English  

    DOI： 10.1093/jb/mvm123

    Web of Science

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Books

  • Go-No-Go：RNA はどこまで転写される？

    中山千尋, 野島孝之（ Role： Joint author）

    実験医学・羊土社  2025 

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  • 新生RNA解析技術からわかるncRNAの転写反応

    中山千尋, 野島孝之（ Role： Joint author）

    実験医学増刊  2024.9 

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  • 哺乳類におけるRNAポリメラーゼIIのC末端ドメインのリン酸化を介する転写と共役したスプライシングの機構

    野島孝之（ Role： Sole author）

    ライフサイエンス新着論文レビュー  2018.11 

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  • ヒトにおけるmRNA前駆体とlincRNAの異なる運命

    野島孝之

    ライフサイエンス新着論文レビュー  2017 

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  • 留学で壁を打ち破る

    野島孝之

    日本RNA学会 寄稿  2016 

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  • 哺乳類NET-seq法：RNAプロセシングと共役した新生転写反応の網羅的解析

    野島孝之

    ライフサイエンス新着論文レビュー  2015 

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  • 次世代新生RNAワールドへ

    野島孝之

    動的クロマチン構造と機能、News letter  2015 

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  • RNAスプライシングの可視化による創薬スクリーニング

    野島孝之, 萩原正敏

    細胞工学  2010 

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  • ウイルスによるスプライシング暗号の利用と撹乱

    野島孝之, 萩原正敏

    実験医学（増刊）  2009 

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  • 遺伝子発現を制御する non-coding RNA

    野島孝之, 萩原正敏

    細胞工学  2006 

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MISC

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Presentations

  • The end of RNA synthesis Invited

    Takayuki Nojima

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    Event date： 2022.10

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

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  • Transcription termination: Forgotten mechanism in RNA synthesis cycle Invited

    Takayuki Nojima

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    Event date： 2022.7

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

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  • Understanding of genome transcription by nascent RNA analysis Invited

    Takayuki Nojima

    CRI seminar, Kanazawa Univrsity  2022.1 

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    Event date： 2022.1

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

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  • POINTing toward transcription termination Invited

    Takayuki Nojima

    30th Hot Spring Harbor Symposium, Chromatin Potential joint symposium  2022.1 

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    Event date： 2022.1

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

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  • Catching mammalian RNA polymerase II in act

    Takayuki Nojima

    RIKEN SAKURA symposium  2017 

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  • Nascent RNA transcription capture by mammalian NET-seq Invited

    Takayuki Nojima

    Chromosome Biology Club, University of Oxford  2015 

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    Language：English  

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  • Nascent RNA world Invited

    Takayuki Nojima

    Toyama RNA club  2017.12 

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    Language：Japanese  

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  • NETting mammalian RNA polymerase II in act Invited

    Takayuki Nojima

    RIKEN DGT seminar  2017 

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    Language：English  

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  • Capturing active Pol II machinery Invited

    Takayuki Nojima

    Riken Seminar  2017.12 

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    Language：Japanese  

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  • Catch RNA polymerase II in transcription cycle Invited

    Takayuki Nojima

    2023.11 

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

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  • 新生RNAから理解する 転写サイクル Invited

    野島孝之

    横浜市立大学医学部セミナー  2024.8 

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

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  • Pol II transcription termination in cancer Invited

    Takayuki Nojima

    Sir William Dunn School of Pathology, University of Oxford  2024.5 

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

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  • RNA Polymerase II転写とヒストン修飾 Invited

    野島孝之

    第18回日本エピジェネティクス研究会  2025.6 

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

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  • Ending Pol II transcription in cancer Invited

    Takayuki Nojima

    ASBMB-MBSJ  2024.12 

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

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  • 転写終結による RNA転写とDNA複製の棲み分け Invited

    野島孝之

    日本分子生物学会  2023.12 

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    Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

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  • 新生RNA解析から理解するゲノム転写サイクル制御 Invited

    第, 回サテライトシンポジウム」RNA, が制御する多様な生命機能

    2023.11 

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

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  • 出来立てのRNAを 調べて分かるゲノム作動 Invited

    野島孝之

    慶應薬学サイヤンスセミナー  2024.1 

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

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  • Ending RNA messages in cancer cells Invited

    Takayuki Nojima

    がん研究所セミナー  2024.1 

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

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  • The orchestration of transcription and coupled RNA processing Invited

    Takayuki Nojima

    2020.12 

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    Presentation type：Oral presentation (invited, special)  

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  • 新生RNAライフサイクルを理解する Invited

    野島孝之

    金沢創発数理セミナー  2022.4 

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

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  • NELF restricts deleterious readthrough RNAs in replicating cells

    野島孝之

    日本RNA学会  2023.7 

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    Language：Japanese   Presentation type：Oral presentation (general)  

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  • Mechanism of Co-transcriptional RNA splicing Invited

    Takayuki Nojima

    KEY FORUM 2021  2021.11 

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

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  • End of RNA synthesis Invited

    Takayuki Nojima

    2021.11 

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

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  • Terminating RNA synthesis in mammalian cells Invited

    Takayuki Nojima

    OIST seminar  2023.7 

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  • 転写終結異常と長鎖非コードRNA産生 Invited

    野島孝之

    日本生化学会  2025.11 

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

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  • リードスルーRNA転写による 細胞周期の停止 Invited

    野島孝之

    日本生化学会  2023.11 

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    Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

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  • Transcription termination to police noncoding RNA synthesis Invited

    Takayuki Nojima

    2025.12 

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

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  • 新生RNA一塩基解像度解析から見えてくるRNAポリメラーゼII転写制御機構 Invited

    野島孝之

    日本大学文理学部生命科学科セミナー 、細胞核機能の発現と制御  2017 

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    Language：Japanese  

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  • Regulation of noncoding transcripion Invited

    Takayuki Nojima

    IFOM (Milan, Italy) lecture  2019.5 

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

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  • Regulation of noncoding transcription for genome maintenace Invited

    Takayuki Nojima

    CRUK Beatson lecture  2018.10 

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

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  • Noncoding transcription and genotoxic stress Invited

    Takayuki Nojima

    2019.8 

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  • Noncoding transcription regulation Invited

    Takayuki Nojima

    Cambrige University, Biochemistry department seminar  2019.7 

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  • Long noncoding transcription and genome stability Invited

    Takayuki Nojima

    MRC London Medical Sciences (LMS) synposium  2018.5 

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  • Regulating Pol II transcription for genome stability Invited

    Takayuki Nojima

    Department seminar, WIMM University of Oxford  2018.3 

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  • Noncoding transcription and genome maintenance Invited

    Takayuki Nojima

    RIKEN IMS symposium  2018.8 

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  • Deregulated expression of lncRNA induces R-loop associated DNA damage and cellular senescence

    Takayuki Nojima

    CSHL, Regulatory & ncRNA  2018.7 

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  • Intact nascent RNA-seq reveals RNA cleavage-mediated transcription termination

    Takayuki Nojima

    CSHL meeting, Regulatory & Non-Coding RNA  2020.5 

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    Presentation type：Oral presentation (general)  

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  • Regulation of genome transcription coupled to RNA processing Invited

    Takayuki Nojima

    MiB seminar , Kyushu University  2019.11 

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  • Catch RNA polymerase II in act; Genome-wide analysis of nascent RNA in mammalian cells Invited

    Takayuki Nojima

    21st Tokyo RNA Club  2016 

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  • Catch RNA polymerase II in act; Genome-wide nascent RNA analysis in mammalian cells Invited

    Takayuki Nojima

    Max Planck Institute symposium  2016 

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Awards

  • ISPF International collaboration Award

    2024.3   The Royal Society   Dissecting transcription termination addiction in cancer

    Michael Tellier, Takayuki Nojima

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  • 文部科学大臣表彰 科学技術賞（研究）

    2023.4   文部科学省   超高解像度新生RNA解析法の開発とゲノム転写制御の研究

    野島孝之

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  • Best poster prize

    2018.2   RNA society UK  

    Takayuki Nojima

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  • Exceptional Achievement Award

    2015   University of Oxford  

    Takayuki Nojima

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  • 海外留学助成リサーチアワード

    2013   公益財団法人 かなえ医薬振興財団  

    野島孝之

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  • 海外留学リサーチフェロー

    2010   上原記念生命科学財団  

    野島孝之

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  • スーパースチュウデントシップ

    2004   東京医科歯科大学 21世紀COE「歯と骨」  

    野島孝之

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Research Projects

  • タンパク質コード遺伝子に埋め込まれた非コード攪乱RNAの産生機構と細胞機能

    Grant number：26H01586  2026.4 - 2028.3

    日本学術振興会  科学研究費助成事業  学術変革領域研究(A)

    野島 孝之

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    Authorship：Principal investigator 

    Grant amount：\4940000 （ Direct Cost: \3800000 、 Indirect Cost：\1140000 ）

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  • Dissecting transcription termination addiction in cancer

    2024.4 - 2028.3

    The Royal Society  ISPF International Collaboration Award (UK-JAPAN) 

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    Authorship：Principal investigator 

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  • 細胞ストレスよる転写終結制御破綻メカニズムの解明

    2024.4 - 2027.3

    日本学術振興会  科学研究費助成事業（基盤Ｂ） 

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  • 転写終結機構の解明とそれ由来生体代謝物の医学的応用

    2024.1 - 2024.12

    公益財団法人 アステラス病態代謝研究会  研究助成 

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  • がん機能性⾮コードRNAの発現を左右する転写終結機構の分⼦解剖と医学的応⽤

    2023.12

    公益財団法人 内藤記念科学振興財団  研究助成 

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  • 非コードRNA産生を制御する転写終結機構の解明

    2023.2

    公益財団法人 三菱財団  自然科学研究助成 

    野島孝之

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    Authorship：Principal investigator 

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  • 非コードRNA異常産生を防ぐ転写終結機構の解明

    2022.12 - 2023.12

    上原記念生命科学財団  2022年度 研究助成金 生命科学部門 

    野島孝之

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  • 非コードRNA機能を調節する転写終結機構の解明

    2022.11

    公益財団法人 武田科学振興財団  生命科学研究助成 

    野島孝之

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    Authorship：Principal investigator 

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  • 遺伝⼦代謝産物の⻑さを決定する未成熟転写終結機構の解明

    2022.11

    公益財団法人 住友財団  基礎科学研究助成 

    野島孝之

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    Authorship：Principal investigator 

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  • 未成熟転写終結を介する非コードRNA代謝物の産生機構と生物学的機能の解明

    2022.10

    公益財団法⼈ ⾦原⼀郎医学医療振興財団  基礎医学医療研究助成金 

    野島孝之

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    Authorship：Principal investigator 

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  • 非コードRNA発現をON/OFFにする転写終結機構の解明とその医学的応用

    2022.7

    公益財団法人 第一三共生命科学研究振興財団  PIセットアップ研究助成 

    野島孝之

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    Authorship：Principal investigator 

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  • がんクロマチン環境における非コードRNA産生機構の解明

    2022.4 - 2025.3

    金沢大学がん進展制御研究所  共同研究助成 

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  • 抗がん化合物で誘導される“未成熟”転写終結制御機構とそれ由来長鎖非コードRNAの生理学的機能解析

    2022.1 - 2023.1

    公益財団法人 高松宮妃癌研究基金  研究助成金 

    野島孝之

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    Authorship：Principal investigator 

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  • 非コードRNAを創出するがん特異的な転写終結機構の解明

    2022

    公益財団法人 ノバルティス科学振興財団  研究助成 

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  • Mechanism of noncoding RNA synthesis though transcription termination and its theraputic application

    2021.11 - 2022.10

    Takayuki Nojima

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    Authorship：Principal investigator 

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  • 新生RNAライフサイクルを制御する転写終結機構の解明

    2021.4 - 2028.3

    JST  創発研究 

    野島孝之

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    Authorship：Principal investigator 

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  • RNAプロセシングと共役するゲノム転写とその破綻機構の解明

    Grant number：19K24692  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業  国際共同研究加速基金(帰国発展研究)

    野島 孝之

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    Grant amount：\55770000 （ Direct Cost: \42900000 、 Indirect Cost：\12870000 ）

    本研究では、細胞核内で起こるRNA polymerase II (Pol II) 転写装置とRNAプロセシング装置のクロストークや非コードゲノム転写制御機構の解明を目標としている。また、RNAプロセシング機構が破綻している骨髄異形性症候群や腎臓がんなどの疾患細胞モデルを用いて、その異常ゲノム転写-RNAプロセシング制御を解析する。このアプローチにより、基礎的なゲノム転写制御機構とがん細胞増殖や細胞分化の解明に貢献する。
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    本研究における第一目標は新生RNA一分子解析法（Polymerase-Intact Nascent Transcript、POINT法）の確立であった。この目標はすでに達成できおり、POINT法を用いて哺乳類細胞でのスプライシングキネティクスや二つのRNAプロセシング（スプライシング-3'end RNA切断）間制御機構を明らかにした（Sousa-Luis et al., Molecular Cell 2021）。
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    また。転写終結機構の解析も順調であり、がんクロマチン環境下での転写終結破綻や抗がん剤処理下での未成熟転写終結由来の非コードRNAの解析をすすめている。2021年度は帰国後の研究室立ち上げに注力し、研究室設備を整備していた。本支援により基本的な実験設備等を整えることができた。それと同時に、非コードRNA転写制御に関する英文総説（Nature Reviews Molecular Cell Biology, 2022）を執筆し、分野内で高い評価を得ている。国際共同研究も精力的に行い、二報がpreprintとして現在公開中である。

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  • 悪性腫瘍特異的なRNA選択的スプライシングを制御する抗がん剤の開発

    Grant number：21200074  2009 - 2011

    日本学術振興会  科学研究費助成事業  新学術領域研究(研究課題提案型)

    野島 孝之

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    Grant amount：\20930000 （ Direct Cost: \16100000 、 Indirect Cost：\4830000 ）

    悪性腫瘍による死亡は増加し続け、2030年には世界で1140万人が悪性腫瘍で死亡すると予測されている。そのため、悪性腫瘍の画期的な治療法の確立は最優先で行われるべき研究のひとつであると考えられる。以前、申請者を含めたグループはRNAスプライシングを標的した抗がん剤候補化合物を報告しており(Nature Chem.Biol., 2007)、スプライシング制御は悪性腫瘍治療の新しいターゲットに成り得ると期待されている。申請者はRNA選択的スプライシング制御により、がん細胞特異的なスプライシングバリアントの生成を抑制することで、がん細胞の種類を問わず効果を発揮する、副作用の少ない画期的な抗がん剤の開発を目指している。最近、解糖系律速酵素のひとつであるピルビン酸キナーゼ(pyruvate kinase type-muscle : PKM)遺伝子の発現制御ががん細胞の増殖に密接に関係していることが報告されたことから、申請者はPKM遺伝子のスプライシングに注目し、研究を遂行してきた。PKM遺伝子はPKM1タンパク質とPKM2タンパク質という2つのアイソフォームを選択的スプライシングによって産生する。正常組織ではエクソン9を含むPKM1、ほとんど全てのがん組織ではエクソン10を含むPKM2が選択されるようになる。申請者は、それぞれのエクソンを選択した際に異なる蛍光タンパク質を発現するレポーターの構築に成功した。このPKMレポーターは、エクソン9を選択する時には緑色蛍光タンパク質GFPを、エクソン10を選択するときには赤色蛍光タンパク質RFPを発現するように設計されている。現在、このレポーターを安定的に発現するマウス筋芽細胞C2C12を樹立している。このPKMレポーター細胞と化合物ライブラリー(購入したFDA認可化合物ライブラリー約700種または東京医科歯科大学の低分子化合物ライブラリー約20,000種)を用いてスクリーニングを始める準備をしているところであり、GFP(正常細胞型)を発現させる化合物の取得を試みている。

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  • ヘルペスウイルス感染による宿主選択的スプライシング制御と免疫回避機構

    2008.4 - 2010.3

    独立行政法人日本学術振興会(JSPS)  若手研究(B) 

    野島孝之

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    Authorship：Principal investigator  Grant type：Competitive

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  • Elucidation of the mechanisms underlying neoantigen production independent of genomic mutation induced by DNA damage

    Grant number：23K18232  2023.6 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

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    Grant amount：\6500000 （ Direct Cost: \5000000 、 Indirect Cost：\1500000 ）

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  • DNA複製・RNA転写コンフリクトのゲノム科学的解析

    Grant number：23K27156  2023.4 - 2026.3

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    大学 保一, 野島 孝之

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    Grant amount：\18720000 （ Direct Cost: \14400000 、 Indirect Cost：\4320000 ）

    本年度は、転写機構の変化に応じて、DNA複製機構が変化するかを検証するための実験系の構築を集中的に実施した。分担者（野島孝之准教授・九州大学）の研究によって、RNAポリメラーゼの制御因子であるNELF複合体の喪失は、転写への影響のみならず、細胞周期の進行にも強く影響を及ぼすことが示されている。このことから、 NELF複合体の機能喪失による転写制御不全は、転写によるＤＮＡ複製への干渉を増大させ、結果として、細胞周期の停止を引き起こすとの仮説を設定し、それを検証している。 NELF複合体の状態に応じて、複製フォークの開始・進行、DNAポリメラーゼの機能が、どのように変化するかを検証するために、NELFCD因子の迅速分解を誘導するシステムをPu-seq実験に使用する細胞株において作成した。現在までにPu-seq実験のデータをえる段階までに至ったはいないが、短期期間内に、この実験を完了できる見込みが立ったところである。

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  • Molecular Mechanism of Inronless mRNA transport

    Grant number：19390071  2007 - 2008

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    HAGIWARA Masatoshi, NOJIMA Takayuki

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    Authorship：Coinvestigator(s) 

    Grant amount：\18980000 （ Direct Cost: \14600000 、 Indirect Cost：\4380000 ）

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  • ヘルペスウイルスRNAの核外輸送制御機構の解明

    Grant number：19041027  2007 - 2008

    日本学術振興会  科学研究費助成事業 特定領域研究  特定領域研究

    萩原 正敏, 小野木 博, 野島 孝之

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    Authorship：Coinvestigator(s) 

    Grant amount：\7500000 （ Direct Cost: \7500000 ）

    単純ヘルペスウイルス2型(HSV-2 ; Herpes Simplex Virus type-2) は世界中に広く伝播しているDNAウイルスで、性器ヘルペスを主症状とする。HSV-2のウイルスゲノム複製は宿主細胞の核内で行われるが、HSV-2ゲノムは宿主染色体には組み込まれず、リング状となり、PML(promyelocytic leukemia protein, TRIM19)を主成分とするドット状の核内構造体ND10(PML body, POD) に取り込まれる。PMLのpre-mRNAは選択的スプライシングを受け7種のPMLアイソフォーム蛋白が産生される。我々はHSV-2感染によって、PNL pre-mRNAの選択的スプライシングが影響を受け、PML蛋白質のアイソフォームが変化することを見出した。すなわち、非感染状態の細胞ではI型とII型PMLが主に発現しているが、HSV-2感染細胞ではV型が主に発現する。この選択的スプライシングの変化をRFPの発現で可視化できるスプライシングレポーターを作成して培養細胞内に導入した。このレポーター細胞では、非感染状態の細胞はRFPが発現するが非感染細胞ではRFPの発現が消失しており、蛍光顕微鏡下で感染・非感染の識別が可能となった。このスプライシングレポーター細胞に種々のウイルス蛋白を発現させてウイルス由来のスプライシング制御因子を検索したところ、核外輸送蛋白ICP27がPML mRNAをII型からV型へ変換していることが判明した。ICP27のRNA認識機構は予想外に複雑であることが判明したので、CLIPと呼ばれる新しい研究手法でICP27の標的遺伝子転写産物の解析を進めている。

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