Details of the Researcher

PHOTO

Shinpei Kawaoka
Section
Institute of Development, Aging and Cancer
Job title
Associate Professor
Degree

  • 博士（農学）（東京大学）

  • 修士（農学）（東京大学）

Profile

Cancer-host interaction and enhancer genetics

Research History 9

  • 2023/10 - Present
    日本学術会議　連携会員

  • 2022/04 - Present
    Kyoto University　Institute for Life and Medical Sciences　Associate Professor

  • 2021/10 - Present
    Tohoku University　Institute of Development, Aging and Cancer

  • 2018/10 - Present
    Kyoto University

  • 2014/04 - 2018/09
    Japan Science and Technology Agency

  • 2014/04 - 2018/09
    Advanced Telecommunications Research Institute International

  • 2012/04 - 2014/03
    コールドスプリングハーバー研究所　博士研究員

  • 2007/04 - 2012/03
    東京大学大学院　農学生命科学研究科　修士課程・博士課程

  • 2003/04 - 2007/03
    The University of Tokyo　College of Arts and Sciences

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Committee Memberships 11

  • 日本生化学会　評議員

    2024/09 - Present

  • 日本カヘキシア・サルコペニア学会　評議員

    2024/07 - Present

  • 第84回日本癌学会学術総会　プログラム委員

    2024/05 - Present

  • 日本癌学会　広報員会: ワーキンググループ

    2024/05 - Present

  • 日本学術会議　機能医科学分科会

    2024/05 - Present

  • 第26回日本RNA学会年会　世話人

    2024/04 - Present

  • 雑誌生化学　企画協力委員

    2024/01 - Present

  • 東北大学加齢医学研究所研究員会　委員長

    2023/12 - Present

  • 日本学術会議　若手アカデミー

    2023/10 - Present

  • 第19回生命医科学研究所ネットワーク国際シンポジウム　運営委員

    2024/04 - 2024/10

  • 奈良県奈良市西登美ヶ丘4丁目　自治会長

    2021/04 - 2022/03

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Research Interests 9

  • Human-device interaction

  • Circadian rhythm

  • Metabolism

  • Cancer cachexia

  • Pathophysiology of cancer-bearing host

  • Immunology

  • Multi-Omics

  • Cancer-host interaction

  • Enhancer genetics

Research Areas 5

  • Life sciences / Pathobiochemistry /

  • Life sciences / Clinical pharmacy /

  • Life sciences / Physiology /

  • Life sciences / Tumor biology /

  • Life sciences / Genomics /

Papers 39

  1. Intra-patient spatial comparison of non-metastatic and metastatic lymph nodes reveals the reduction of CD169+ macrophages by metastatic breast cancers. International-journal

    Yurina Maeshima, Tatsuki R Kataoka, Alexis Vandenbon, Masahiro Hirata, Yasuhide Takeuchi, Yutaka Suzuki, Yukiko Fukui, Masahiro Kawashima, Masahiro Takada, Yumiko Ibi, Hironori Haga, Satoshi Morita, Masakazu Toi, Shinpei Kawaoka, Kosuke Kawaguchi

    EBioMedicine　107　105271-105271　2024/09

    DOI： 10.1016/j.ebiom.2024.105271 　

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    BACKGROUND: Breast cancer cells suppress the host immune system to efficiently invade the lymph nodes; however, the underlying mechanism remains incompletely understood. Here, we aimed to comprehensively characterise the effects of breast cancers on immune cells in the lymph nodes. METHODS: We collected non-metastatic and metastatic lymph node samples from 6 patients with breast cancer with lymph node metastasis. We performed bulk transcriptomics, spatial transcriptomics, and imaging mass cytometry to analyse the obtained lymph nodes. Furthermore, we conducted histological analyses against a larger patient cohort (474 slices from 58 patients). FINDINGS: The comparison between paired lymph nodes with and without metastasis from the same patients demonstrated that the number of CD169+ lymph node sinus macrophages, an initiator of anti-cancer immunity, was reduced in metastatic lymph nodes (36.7 ± 21.1 vs 7.3 ± 7.0 cells/mm2, p = 0.0087), whereas the numbers of other major immune cell types were unaltered. We also detected that the infiltration of CD169+ macrophages into metastasised cancer tissues differed by section location within tumours, suggesting that CD169+ macrophages were gradually decreased after anti-cancer reactions. Furthermore, CD169+ macrophage elimination was prevalent in major breast cancer subtypes and correlated with breast cancer staging (p = 0.022). INTERPRETATION: We concluded that lymph nodes with breast cancer metastases have fewer CD169+ macrophages, which may be detrimental to the activity of anti-cancer immunity. FUNDING: JSPS KAKENHI (16H06279, 20H03451, 20H04842, 22H04925, 19K16770, and 21K15530, 24K02236), JSPS Fellows (JP22KJ1822), AMED (JP21ck0106698), JST FOREST (JPMJFR2062), Caravel, Co., Ltd, Japan Foundation for Applied Enzymology, and Sumitomo Pharma Co., Ltd. under SKIPS.

  2. An atlas of transcribed enhancers across helper T cell diversity for decoding human diseases. International-journal

    Akiko Oguchi, Akari Suzuki, Shuichiro Komatsu, Hiroyuki Yoshitomi, Shruti Bhagat, Raku Son, Raoul Jean Pierre Bonnal, Shohei Kojima, Masaru Koido, Kazuhiro Takeuchi, Keiko Myouzen, Gyo Inoue, Tomoya Hirai, Hiromi Sano, Yujiro Takegami, Ai Kanemaru, Itaru Yamaguchi, Yuki Ishikawa, Nao Tanaka, Shigeki Hirabayashi, Riyo Konishi, Sho Sekito, Takahiro Inoue, Juha Kere, Shunichi Takeda, Akifumi Takaori-Kondo, Itaru Endo, Shinpei Kawaoka, Hideya Kawaji, Kazuyoshi Ishigaki, Hideki Ueno, Yoshihide Hayashizaki, Massimiliano Pagani, Piero Carninci, Motoko Yanagita, Nicholas Parrish, Chikashi Terao, Kazuhiko Yamamoto, Yasuhiro Murakawa

    Science (New York, N.Y.)　385　(6704)　eadd8394　2024/07/05

    DOI： 10.1126/science.add8394 　

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    Transcribed enhancer maps can reveal nuclear interactions underpinning each cell type and connect specific cell types to diseases. Using a 5' single-cell RNA sequencing approach, we defined transcription start sites of enhancer RNAs and other classes of coding and noncoding RNAs in human CD4+ T cells, revealing cellular heterogeneity and differentiation trajectories. Integration of these datasets with single-cell chromatin profiles showed that active enhancers with bidirectional RNA transcription are highly cell type-specific and that disease heritability is strongly enriched in these enhancers. The resulting cell type-resolved multimodal atlas of bidirectionally transcribed enhancers, which we linked with promoters using fine-scale chromatin contact maps, enabled us to systematically interpret genetic variants associated with a range of immune-mediated diseases.

  3. Progressive, multi-organ, and multi-layered nature of cancer cachexia. International-journal

    Yuki Nakamura, Don Pietro Saldajeno, Kosuke Kawaguchi, Shinpei Kawaoka

    Cancer science　2024/01/22

    DOI： 10.1111/cas.16078 　

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    Cancer cachexia is a complex, multifaceted condition that negatively impacts the health, treatment efficacy, and economic status of cancer patients. The management of cancer cachexia is an essential clinical need. Cancer cachexia is currently defined mainly according to the severity of weight loss and sarcopenia (i.e., macrosymptoms). However, such macrosymptoms may be insufficient to give clinicians clues on how to manage this condition as these symptoms appear at the late stage of cancer. We need to understand earlier events during the progression of cancer cachexia so as not to miss a clinical opportunity to control this complex syndrome. Recent research indicates that cancer-induced changes in the host are much wider than previously recognized, including disruption of liver function and the immune system. Furthermore, such changes are observed before the occurrence of visible distant metastases (i.e., in early, localized cancers). In light of these findings, we propose to expand the definition of cancer cachexia to include all cancer-induced changes to host physiology, including changes caused by early, localized cancers. This new definition of cancer cachexia can provide a new perspective on this topic, which can stimulate the research and development of novel cancer cachexia therapies.

  4. Time-series blood cytokine profiles correlate with treatment responses in triple-negative breast cancer patients. International-journal

    Don Pietro Saldajeno, Shinpei Kawaoka, Norikazu Masuda, Sunao Tanaka, Hiroko Bando, Tomomi Nishimura, Takayuki Kadoya, Takashi Yamanaka, Shigeru Imoto, Ravindranath M Velaga, Nobuko Tamura, Tomoyuki Aruga, Kazushi Ikeda, Yukiko Fukui, Yurina Maeshima, Masahiro Takada, Eiji Suzuki, Takayuki Ueno, Seishi Ogawa, Hironori Haga, Shinji Ohno, Satoshi Morita, Kosuke Kawaguchi, Masakazu Toi

    British journal of cancer　2024/01/18

    DOI： 10.1038/s41416-023-02527-0 　

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    BACKGROUND: Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype. Partly due to its heterogeneity, it is currently challenging to stratify TNBC patients and predict treatment outcomes. METHODS: In this study, we examined blood cytokine profiles of TNBC patients throughout treatments (pre-treatment, during chemotherapy, pre-surgery, and 1 year after the surgery in a total of 294 samples). We analyzed the obtained cytokine datasets using weighted correlation network analyses, protein-protein interaction analyses, and logistic regression analyses. RESULTS: We identified five cytokines that correlate with good clinical outcomes: interleukin (IL)-1α, TNF-related apoptosis-inducing ligand (TRAIL), Stem Cell Factor (SCF), Chemokine ligand 5 (CCL5 also known as RANTES), and IL-16. The expression of these cytokines was decreased during chemotherapy and then restored after the treatment. Importantly, patients with good clinical outcomes had constitutively high expression of these cytokines during treatments. Protein-protein interaction analyses implicated that these five cytokines promote an immune response. Logistic regression analyses revealed that IL-1α and TRAIL expression levels at pre-treatment could predict treatment outcomes in our cohort. CONCLUSION: We concluded that time-series cytokine profiles in breast cancer patients may be useful for understanding immune cell activity during treatment and for predicting treatment outcomes, supporting precision medicine. TRIAL REGISTRATION: The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with the unique trial number UMIN000023162. The association Japan Breast Cancer Research Group trial number is JBCRG-22. The clinical outcome of the JBCRG-22 study was published in Breast Cancer Research and Treatment on 25 March 2021. https://doi.org/10.1007/s10549-021-06184-w .

  5. Nicotinamide-N-methyltransferase regulates lipid metabolism via SAM and 1-methylnicotinamide in the AML12 hepatocyte cell line. International-journal

    Mayuko Yoda, Rin Mizuno, Yoshihiro Izumi, Masatomo Takahashi, Takeshi Bamba, Shinpei Kawaoka

    Journal of biochemistry　174　(1)　89-98　2023/04/04

    DOI： 10.1093/jb/mvad028 　

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    Nicotinamide-N-methyltransferase (NNMT) is an enzyme that consumes S-adenosyl-methionine (SAM) and nicotinamide (NAM) to produce S-adenosyl-homocysteine (SAH) and 1-methylnicotinamide (MNAM). How much NNMT contributes to the quantity regulation of these four metabolites depends on whether NNMT is a major consumer or producer of these metabolites, which varies among various cellular contexts. Yet, whether NNMT critically regulates these metabolites in the AML12 hepatocyte cell line has been unexplored. To address this, we knock down Nnmt in AML12 cells and investigate the effects of Nnmt RNAi on metabolism and gene expression. We find that Nnmt RNAi accumulates SAM and SAH, whereas it reduces MNAM with NAM being unaltered. These results indicate that NNMT is a significant consumer of SAM and critical for MNAM production in this cell line. Moreover, transcriptome analyses reveal that altered SAM and MNAM homeostasis is accompanied by various detrimental molecular phenotypes, as exemplified by the down-regulations of lipogenic genes such as Srebf1. Consistent with this, oil-red O-staining experiments demonstrate the decrease of total neutral lipids upon Nnmt RNAi. Treating Nnmt RNAi AML12 cells with cycloleucine, an inhibitor of SAM biogenesis suppresses SAM accumulation and rescues the decrease of neutral lipids. MNAM also shows activity to elevate neutral lipids. These results suggest that NNMT contributes to lipid metabolism by maintaining proper SAM and MNAM homeostasis. This study provides an additional example where NNMT plays a critical role in regulating SAM and MNAM metabolism.

  6. Murine breast cancers disorganize the liver transcriptome in a zonated manner. International-journal

    Alexis Vandenbon, Rin Mizuno, Riyo Konishi, Masaya Onishi, Kyoko Masuda, Yuka Kobayashi, Hiroshi Kawamoto, Ayako Suzuki, Chenfeng He, Yuki Nakamura, Kosuke Kawaguchi, Masakazu Toi, Masahito Shimizu, Yasuhito Tanaka, Yutaka Suzuki, Shinpei Kawaoka

    Communications biology　6　(1)　97-97　2023/01/24

    DOI： 10.1038/s42003-023-04479-w 　

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    The spatially organized gene expression program within the liver specifies hepatocyte functions according to their relative distances to the bloodstream (i.e., zonation), contributing to liver homeostasis. Despite the knowledge that solid cancers remotely disrupt liver homeostasis, it remains unexplored whether solid cancers affect liver zonation. Here, using spatial transcriptomics, we thoroughly investigate the abundance and zonation of hepatic genes in cancer-bearing mice. We find that breast cancers affect liver zonation in various distinct manners depending on biological pathways. Aspartate metabolism and triglyceride catabolic processes retain relatively intact zonation patterns, but the zonation of xenobiotic catabolic process genes exhibits a strong disruption. The acute phase response is induced in zonated manners. Furthermore, we demonstrate that breast cancers activate innate immune cells in particular neutrophils in distinct zonated manners, rather than in a uniform fashion within the liver. Collectively, breast cancers disorganize hepatic transcriptomes in zonated manners, thereby disrupting zonated functions of the liver.

  7. Serum amyloid alpha 1-2 are not required for liver inflammation in the 4T1 murine breast cancer model. International-journal

    Chenfeng He, Riyo Konishi, Ayano Harata, Yuki Nakamura, Rin Mizuno, Mayuko Yoda, Masakazu Toi, Kosuke Kawaguchi, Shinpei Kawaoka

    Frontiers in immunology　14　1097788-1097788　2023

    DOI： 10.3389/fimmu.2023.1097788 　

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    Cancers induce the production of acute phase proteins such as serum amyloid alpha (SAA) in the liver and cause inflammation in various host organs. Despite the well-known coincidence of acute phase response and inflammation, the direct roles of SAA proteins in inflammation in the cancer context remains incompletely characterized, particularly in vivo. Here, we investigate the in vivo significance of SAA proteins in liver inflammation in the 4T1 murine breast cancer model. 4T1 cancers elevate the expression of SAA1 and SAA2, the two major murine acute phase proteins in the liver. The elevation of Saa1-2 correlates with the up-regulation of immune cell-related genes including neutrophil markers. To examine this correlation in detail, we generate mice that lack Saa1-2 and investigate immune-cell phenotypes. RNA-seq experiments reveal that deletion of Saa1-2 does not strongly affect 4T1-induced activation of immune cell-related genes in the liver. Flow cytometry experiments demonstrate the dispensable roles of SAA1-2 in cancer-dependent neutrophil infiltration to the liver. Consistently, 4T1-induced gene expression changes in bone marrow do not require Saa1-2. This study clarifies the negligible contribution of SAA1-2 proteins in liver inflammation in the 4T1 breast cancer model.

  8. Tracing the evolutionary history of blood cells to the unicellular ancestor of animals International-journal

    Yosuke Nagahata, Kyoko Masuda, Yuji Nishimura, Tomokatsu Ikawa, Shinpei Kawaoka, Toshio Kitawaki, Yasuhito Nannya, Seishi Ogawa, Hiroshi Suga, Yutaka Satou, Akifumi Takaori-Kondo, Hiroshi Kawamoto

    Blood　140　(24)　2611-2625　2022/12/15

    Publisher: American Society of Hematology

    DOI： 10.1182/blood.2022016286 　

    ISSN： 0006-4971

    eISSN： 1528-0020

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    Abstract Blood cells are thought to have emerged as phagocytes in the common ancestor of animals followed by the appearance of novel blood cell lineages such as thrombocytes, erythrocytes, and lymphocytes, during evolution. However, this speculation is not based on genetic evidence and it is still possible to argue that phagocytes in different species have different origins. It also remains to be clarified how the initial blood cells evolved; whether ancient animals have solely developed de novo programs for phagocytes or they have inherited a key program from ancestral unicellular organisms. Here, we traced the evolutionary history of blood cells, and cross-species comparison of gene expression profiles revealed that phagocytes in various animal species and Capsaspora (C.) owczarzaki, a unicellular organism, are transcriptionally similar to each other. We also found that both phagocytes and C. owczarzaki share a common phagocytic program, and that CEBPα is the sole transcription factor highly expressed in both phagocytes and C. owczarzaki. We further showed that the function of CEBPα to drive phagocyte program in nonphagocytic blood cells has been conserved in tunicate, sponge, and C. owczarzaki. We finally showed that, in murine hematopoiesis, repression of CEBPα to maintain nonphagocytic lineages is commonly achieved by polycomb complexes. These findings indicate that the initial blood cells emerged inheriting a unicellular organism program driven by CEBPα and that the program has also been seamlessly inherited in phagocytes of various animal species throughout evolution.

  9. Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase. International-journal

    Rin Mizuno, Hiroaki Hojo, Masatomo Takahashi, Soshiro Kashio, Sora Enya, Motonao Nakao, Riyo Konishi, Mayuko Yoda, Ayano Harata, Junzo Hamanishi, Hiroshi Kawamoto, Masaki Mandai, Yutaka Suzuki, Masayuki Miura, Takeshi Bamba, Yoshihiro Izumi, Shinpei Kawaoka

    Nature communications　13　(1)　3346-3346　2022/06/15

    DOI： 10.1038/s41467-022-30926-z 　

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    Cancers disrupt host homeostasis in various manners but the identity of host factors underlying such disruption remains largely unknown. Here we show that nicotinamide-N-methyltransferase (NNMT) is a host factor that mediates metabolic dysfunction in the livers of cancer-bearing mice. Multiple solid cancers distantly increase expression of Nnmt and its product 1-methylnicotinamide (MNAM) in the liver. Multi-omics analyses reveal suppression of the urea cycle accompanied by accumulation of amino acids, and enhancement of uracil biogenesis in the livers of cancer-bearing mice. Importantly, genetic deletion of Nnmt leads to alleviation of these metabolic abnormalities, and buffers cancer-dependent weight loss and reduction of the voluntary wheel-running activity. Our data also demonstrate that MNAM is capable of affecting urea cycle metabolites in the liver. These results suggest that cancers up-regulate the hepatic NNMT pathway to rewire liver metabolism towards uracil biogenesis rather than nitrogen disposal via the urea cycle, thereby disrupting host homeostasis.

  10. Identification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection. International-journal Peer-reviewed

    Miki Arai Hojo, Kyoko Masuda, Hiroaki Hojo, Yosuke Nagahata, Keiko Yasuda, Daiya Ohara, Yusuke Takeuchi, Keiji Hirota, Yutaka Suzuki, Hiroshi Kawamoto, Shinpei Kawaoka

    Nature communications　10　(1)　2603-2603　2019/06/13

    DOI： 10.1038/s41467-019-10525-1 　

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    During thymic negative selection, autoreactive thymocytes carrying T cell receptor (TCR) with overtly strong affinity to self-MHC/self-peptide are removed by Bim-dependent apoptosis, but how Bim is specifically regulated to link TCR activation and apoptosis induction is unclear. Here we identify a murine T cell-specific genomic enhancer EBAB (Bub1-Acoxl-Bim), whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, EBAB knockout mice have defective negative selection and fail to delete autoreactive thymocytes in various settings, with this defect accompanied by reduced Bim expression and apoptosis induction. By contrast, EBAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate EBAB as an important, developmental stage-specific regulator of Bim expression and apoptosis induction to enforce thymic negative selection and suppress autoimmunity. Our study unravels a part of genomic enhancer codes that underlie complex and context-dependent gene regulation in TCR signaling.

  11. A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor-liver crosstalk in causing adverse effects on the host. International-journal Peer-reviewed

    Sora Enya, Koichi Kawakami, Yutaka Suzuki, Shinpei Kawaoka

    Disease models & mechanisms　11　(8)　2018/05/03

    DOI： 10.1242/dmm.032383 　

    ISSN： 1754-8403

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    The nature of host organs and genes that underlie tumor-induced physiological disruption on the host remains ill-defined. Here, we establish a novel zebrafish intestinal tumor model that is suitable for addressing this issue, and find that hepatic cyp7a1, the rate-limiting factor for synthesizing bile acids [or, in the case of zebrafish, bile alcohol (BA)], is such a host gene. Inducing krasG12D by Gal4 specifically expressed in the posterior intestine resulted in the formation of an intestinal tumor. The local intestinal tumor caused systemic detrimental effects on the host, including liver inflammation, hepatomegaly, growth defects and organismal death. Whole-organism-level gene expression analysis and metabolite measurements revealed that the intestinal tumor reduced total BA levels, possibly via altered expression of hepatic cyp7a1 Genetically overexpressing cyp7a1 in the liver restored BA synthesis and ameliorated tumor-induced liver inflammation, but not other tumor-dependent phenotypes. Thus, we found a previously unknown role of cyp7a1 as the host gene that links the intestinal tumor, hepatic cholesterol-BA metabolism and liver inflammation in tumor-bearing zebrafish larvae. Our model provides an important basis to discover host genes responsible for tumor-induced phenotypes and to uncover mechanisms underlying how tumors adversely affect host organisms.

  12. Remote reprogramming of hepatic circadian transcriptome by breast cancer Peer-reviewed

    Hiroaki Hojo, Sora Enya, Miki Arai, Yutaka Suzuki, Takashi Nojiri, Kenji Kangawa, Shinsuke Koyama, Shinpei Kawaoka

    ONCOTARGET　8　(21)　34128-34140　2017/05

    DOI： 10.18632/oncotarget.16699 　

    ISSN： 1949-2553

  13. Histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia Peer-reviewed

    Eric Wang, Shinpei Kawaoka, Ming Yu, Junwei Shi, Ting Ni, Wenjing Yang, Jun Zhu, Robert G. Roeder, Christopher R. Vakoc

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　110　(10)　3901-3906　2013/03

    DOI： 10.1073/pnas.1301045110 　

    ISSN： 0027-8424

  14. 3 ' End Formation of PIWI-Interacting RNAs In Vitro Peer-reviewed

    Shinpei Kawaoka, Natsuko Izumi, Susumu Katsuma, Yukihide Tomari

    MOLECULAR CELL　43　(6)　1015-1022　2011/09

    DOI： 10.1016/j.molcel.2011.07.029 　

    ISSN： 1097-2765

  15. Serum amyloid alpha 1-2 are not required for systemic inflammation in the 4T1 murine breast cancer model

    Chenfeng He, Riyo Konishi, Ayano Harata, Yuki Nakamura, Rin Mizuno, Mayuko Yoda, Masakazu Toi, Kosuke Kawaguchi, Shinpei Kawaoka

    2022/09/28

    DOI： 10.1101/2022.09.26.509617 　

  16. Hsp90 facilitates accurate loading of precursor piRNAs into PIWI proteins (vol 19, pg 896, 2013) Peer-reviewed

    Natsuko Izumi, Shinpei Kawaoka, Satoshi Yasuhara, Yutaka Suzuki, Sumio Sugano, Susumu Katsuma, Yukihide Tomari

    RNA　21　(6)　1217-1217　2015/06

    DOI： 10.1261/rna.052308.115 　

    ISSN： 1355-8382

    eISSN： 1469-9001

  17. The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer Peer-reviewed

    Eric Wang, Shinpei Kawaoka, Jae-Seok Roe, Junwei Shi, Anja F. Hohmann, Yali Xu, Anand S. Bhagwat, Yutaka Suzuki, Justin B. Kinney, Christopher R. Vakoc

    ELIFE　4　e06377　2015/04

    DOI： 10.7554/eLife.06377 　

    ISSN： 2050-084X

  18. Silkworm HP1a transcriptionally enhances highly expressed euchromatic genes via association with their transcription start sites. International-journal Peer-reviewed

    Keisuke Shoji, Kahori Hara, Munetaka Kawamoto, Takashi Kiuchi, Shinpei Kawaoka, Sumio Sugano, Toru Shimada, Yutaka Suzuki, Susumu Katsuma

    Nucleic acids research　42　(18)　11462-71　2014/10

    Publisher: 18

    DOI： 10.1093/nar/gku862 　

    ISSN： 0305-1048

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    Heterochromatin protein 1 (HP1) is an evolutionarily conserved protein across different eukaryotic species and is crucial for heterochromatin establishment and maintenance. The silkworm, Bombyx mori, encodes two HP1 proteins, BmHP1a and BmHP1b. In order to investigate the role of BmHP1a in transcriptional regulation, we performed genome-wide analyses of the transcriptome, transcription start sites (TSSs), chromatin modification states and BmHP1a-binding sites of the silkworm ovary-derived BmN4 cell line. We identified a number of BmHP1a-binding loci throughout the silkworm genome and found that these loci included TSSs and frequently co-occurred with neighboring euchromatic histone modifications. In addition, we observed that genes with BmHP1a-associated TSSs were relatively highly expressed in BmN4 cells. RNA interference-mediated BmHP1a depletion resulted in the transcriptional repression of highly expressed genes with BmHP1a-associated TSSs, whereas genes not coupled with BmHP1a-binding regions were less affected by the treatment. These results demonstrate that BmHP1a binds near TSSs of highly expressed euchromatic genes and positively regulates their expression. Our study revealed a novel mode of transcriptional regulation mediated by HP1 proteins.

  19. A single female-specific piRNA is the primary determiner of sex in the silkworm. International-journal Peer-reviewed

    Takashi Kiuchi, Hikaru Koga, Munetaka Kawamoto, Keisuke Shoji, Hiroki Sakai, Yuji Arai, Genki Ishihara, Shinpei Kawaoka, Sumio Sugano, Toru Shimada, Yutaka Suzuki, Masataka G Suzuki, Susumu Katsuma

    Nature　509　(7502)　633-6　2014/05/29

    Publisher: 7502

    DOI： 10.1038/nature13315 　

    ISSN： 0028-0836

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    The silkworm Bombyx mori uses a WZ sex determination system that is analogous to the one found in birds and some reptiles. In this system, males have two Z sex chromosomes, whereas females have Z and W sex chromosomes. The silkworm W chromosome has a dominant role in female determination, suggesting the existence of a dominant feminizing gene in this chromosome. However, the W chromosome is almost fully occupied by transposable element sequences, and no functional protein-coding gene has been identified so far. Female-enriched PIWI-interacting RNAs (piRNAs) are the only known transcripts that are produced from the sex-determining region of the W chromosome, but the function(s) of these piRNAs are unknown. Here we show that a W-chromosome-derived, female-specific piRNA is the feminizing factor of B. mori. This piRNA is produced from a piRNA precursor which we named Fem. Fem sequences were arranged in tandem in the sex-determining region of the W chromosome. Inhibition of Fem-derived piRNA-mediated signalling in female embryos led to the production of the male-specific splice variants of B. mori doublesex (Bmdsx), a gene which acts at the downstream end of the sex differentiation cascade. A target gene of Fem-derived piRNA was identified on the Z chromosome of B. mori. This gene, which we named Masc, encoded a CCCH-type zinc finger protein. We show that the silencing of Masc messenger RNA by Fem piRNA is required for the production of female-specific isoforms of Bmdsx in female embryos, and that Masc protein controls both dosage compensation and masculinization in male embryos. Our study characterizes a single small RNA that is responsible for primary sex determination in the WZ sex determination system.

  20. Making piRNAs in vitro Peer-reviewed

    Shinpei Kawaoka, Susumu Katsuma, Yukihide Tomari

    Methods in Molecular Biology　1093　35-46　2014

    Publisher: Humana Press Inc.

    DOI： 10.1007/978-1-62703-694-8_4 　

    ISSN： 1064-3745

  21. Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation Peer-reviewed

    Junwei Shi, Warren A. Whyte, Cinthya J. Zepeda-Mendoza, Joseph P. Milazzo, Chen Shen, Jae-Seok Roe, Jessica L. Minder, Fatih Mercan, Eric Wang, Melanie A. Eckersley-Maslin, Amy E. Campbell, Shinpei Kawaoka, Sarah Shareef, Zhu Zhu, Jude Kendall, Matthias Muhar, Christian Haslinger, Ming Yu, Robert G. Roeder, Michael H. Wigler, Gerd A. Blobel, Johannes Zuber, David L. Spector, Richard A. Young, Christopher R. Vakoc

    GENES & DEVELOPMENT　27　(24)　2648-2662　2013/12

    DOI： 10.1101/gad.232710.113 　

    ISSN： 0890-9369

    eISSN： 1549-5477

  22. Characterization of a novel chromodomain-containing gene from the silkworm, Bombyx mori. International-journal Peer-reviewed

    Keisuke Shoji, Takashi Kiuchi, Kahori Hara, Munetaka Kawamoto, Shinpei Kawaoka, Shin-Ichi Arimura, Nobuhiro Tsutsumi, Sumio Sugano, Yutaka Suzuki, Toru Shimada, Susumu Katsuma

    Gene　527　(2)　649-54　2013/09/25

    Publisher: 2

    DOI： 10.1016/j.gene.2013.06.071 　

    ISSN： 0378-1119

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    Heterochromatin protein 1 (HP1) is an evolutionarily conserved protein across different eukaryotic species, and is crucial in the establishment and maintenance of heterochromatin. HP1 proteins have two distinct functional domains, an N-terminal chromodomain (CD) and a C-terminal chromoshadow domain (CSD), which are required for the selective binding of HP1 proteins to modified histones. During our screen for HP1-like proteins in the Bombyx mori genome, we found a novel silkworm gene, Bombyx mori chromodomain protein 1 (BmCdp1), encoding a putative chromobox protein with only two CDs. The BmCdp1 family proteins are closely related to the HP1 proteins, and most of them belong to insect lineages. qRT-PCR analysis indicated that BmCdp1 mRNA was most abundantly expressed in early embryos, and relatively higher expression was observed in larval testes, hemocytes, and pupal ovaries. Western blot and immunostaining experiments showed that BmCdp1 was localized mainly in the nucleus of BmN4 cells. We searched BmCdp1-bound loci in the Bombyx genome by ChIP-seq analysis using Flag-tagged BmCdp1-expressing BmN4 cells. Combined with ChIP-qPCR experiments, we identified two reliable BmCdp1-bound loci in the genome. siRNA-mediated knockdown of BmCdp1 in BmN4 cells and early embryos did not affect the expression of the gene located close to the BmCdp1-bound locus.

  23. Large scale full-length cDNA sequencing reveals a unique genomic landscape in a lepidopteran model insect, Bombyx mori. International-journal Peer-reviewed

    Suetsugu Y, Futahashi R, Kanamori H, Kadono-Okuda K, Sasanuma S, Narukawa J, Ajimura M, Jouraku A, Namiki N, Shimomura M, Sezutsu H, Osanai-Futahashi M, Suzuki MG, Daimon T, Shinoda T, Taniai K, Asaoka K, Niwa R, Kawaoka S, Katsuma S, Tamura T, Noda H, Kasahara M, Sugano S, Suzuki Y, Fujiwara H, Kataoka H, Arunkumar KP, Tomar A, Nagaraju J, Goldsmith MR, Feng Q, Xia Q, Yamamoto K, Shimada T, Mita K

    G3 (Bethesda, Md.)　3　(9)　1481-1492　2013/09

    Publisher: 9

    DOI： 10.1534/g3.113.006239 　

    More details Close

    The establishment of a complete genomic sequence of silkworm, the model species of Lepidoptera, laid a foundation for its functional genomics. A more complete annotation of the genome will benefit functional and comparative studies and accelerate extensive industrial applications for this insect. To realize these goals, we embarked upon a large-scale full-length cDNA collection from 21 full-length cDNA libraries derived from 14 tissues of the domesticated silkworm and performed full sequencing by primer walking for 11,104 full-length cDNAs. The large average intron size was 1904 bp, resulting from a high accumulation of transposons. Using gene models predicted by GLEAN and published mRNAs, we identified 16,823 gene loci on the silkworm genome assembly. Orthology analysis of 153 species, including 11 insects, revealed that among three Lepidoptera including Monarch and Heliconius butterflies, the 403 largest silkworm-specific genes were composed mainly of protective immunity, hormone-related, and characteristic structural proteins. Analysis of testis-/ovary-specific genes revealed distinctive features of sexual dimorphism, including depletion of ovary-specific genes on the Z chromosome in contrast to an enrichment of testis-specific genes. More than 40% of genes expressed in specific tissues mapped in tissue-specific chromosomal clusters. The newly obtained FL-cDNA sequences enabled us to annotate the genome of this lepidopteran model insect more accurately, enhancing genomic and functional studies of Lepidoptera and comparative analyses with other insect orders, and yielding new insights into the evolution and organization of lepidopteran-specific genes.

  24. Hsp90 facilitates accurate loading of precursor piRNAs into PIWI proteins Peer-reviewed

    Natsuko Izumi, Shinpei Kawaoka, Satoshi Yasuhara, Yutaka Suzuki, Sumio Sugano, Susumu Katsuma, Yukihide Tomari

    RNA-A PUBLICATION OF THE RNA SOCIETY　19　(7)　896-901　2013/07

    DOI： 10.1261/rna.037200.112 　

    ISSN： 1355-8382

  25. The comprehensive epigenome map of piRNA clusters. International-journal Peer-reviewed

    Shinpei Kawaoka, Kahori Hara, Keisuke Shoji, Maki Kobayashi, Toru Shimada, Sumio Sugano, Yukihide Tomari, Yutaka Suzuki, Susumu Katsuma

    Nucleic acids research　41　(3)　1581-90　2013/02/01

    Publisher: 3

    DOI： 10.1093/nar/gks1275 　

    ISSN： 0305-1048

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    PIWI-interacting RNA (piRNA) clusters act as anti-transposon/retrovirus centers. Integration of selfish jumping elements into piRNA clusters generates de novo piRNAs, which in turn exert trans-silencing activity against these elements in animal gonads. To date, neither genome-wide chromatin modification states of piRNA clusters nor a mode for piRNA precursor transcription have been well understood. Here, to understand the chromatin landscape of piRNA clusters and how piRNA precursors are generated, we analyzed the transcriptome, transcription start sites (TSSs) and the chromatin landscape of the BmN4 cell line, which harbors the germ-line piRNA pathway. Notably, our epigenomic map demonstrated the highly euchromatic nature of unique piRNA clusters. RNA polymerase II was enriched for TSSs that transcribe piRNA precursors. piRNA precursors possessed 5'-cap structures as well as 3'-poly A-tails. Collectively, we envision that the euchromatic, opened nature of unique piRNA clusters or piRNA cluster-associated TSSs allows piRNA clusters to capture new insertions efficiently.

  26. Altered expression of testis-specific genes, piRNAs, and transposons in the silkworm ovary masculinized by a W chromosome mutation Peer-reviewed

    Kahori Hara, Tsuguru Fujii, Yutaka Suzuki, Sumio Sugano, Toru Shimada, Susumu Katsuma, Shinpei Kawaoka

    BMC GENOMICS　13　119　2012/03

    DOI： 10.1186/1471-2164-13-119 　

    ISSN： 1471-2164

  27. A role for transcription from a piRNA cluster in de novo piRNA production Peer-reviewed

    Shinpei Kawaoka, Hiroshi Mitsutake, Takashi Kiuchi, Maki Kobayashi, Mayu Yoshikawa, Yutaka Suzuki, Sumio Sugano, Toru Shimada, Jun Kobayashi, Yukihide Tomari, Susumu Katsuma

    RNA-A PUBLICATION OF THE RNA SOCIETY　18　(2)　265-273　2012/02

    DOI： 10.1261/rna.029777.111 　

    ISSN： 1355-8382

  28. The silkworm W chromosome is a source of female-enriched piRNAs Peer-reviewed

    Shinpei Kawaoka, Koji Kadota, Yuji Arai, Yutaka Suzuki, Tsuguru Fujii, Hiroaki Abe, Yuji Yasukochi, Kazuei Mita, Sumio Sugano, Kentaro Shimizu, Yukihide Tomari, Toru Shimada, Susumu Katsuma

    RNA-A PUBLICATION OF THE RNA SOCIETY　17　(12)　2144-2151　2011/12

    DOI： 10.1261/rna.027565.111 　

    ISSN： 1355-8382

  29. Zygotic amplification of secondary piRNAs during silkworm embryogenesis Peer-reviewed

    Shinpei Kawaoka, Yuji Arai, Koji Kadota, Yutaka Suzuki, Kahori Hara, Sumio Sugano, Kentaro Shimizu, Yukihide Tomari, Toru Shimada, Susumu Katsuma

    RNA-A PUBLICATION OF THE RNA SOCIETY　17　(7)　1401-1407　2011/07

    DOI： 10.1261/rna.2709411 　

    ISSN： 1355-8382

  30. Non-molting glossy/shroud encodes a short-chain dehydrogenase/reductase that functions in the 'Black Box' of the ecdysteroid biosynthesis pathway Peer-reviewed

    Ryusuke Niwa, Toshiki Namiki, Katsuhiko Ito, Yuko Shimada-Niwa, Makoto Kiuchi, Shinpei Kawaoka, Takumi Kayukawa, Yutaka Banno, Yoshinori Fujimoto, Shuji Shigenobu, Satoru Kobayashi, Toru Shimada, Susumu Katsuma, Tetsuro Shinoda

    DEVELOPMENT　137　(12)　1991-1999　2010/06

    DOI： 10.1242/dev.045641 　

    ISSN： 0950-1991

  31. The Bombyx ovary-derived cell line endogenously expresses PIWI/PIWI-interacting RNA complexes Peer-reviewed

    Shinpei Kawaoka, Nobumitsu Hayashi, Yutaka Suzuki, Hiroaki Abe, Sumio Sugano, Yukihide Tomari, Toru Shimada, Susumu Katsuma

    RNA-A PUBLICATION OF THE RNA SOCIETY　15　(7)　1258-1264　2009/07

    DOI： 10.1261/rna.1452209 　

    ISSN： 1355-8382

  32. Identification and characterization of globin genes from two lepidopteran insects, Bombyx mori and Samia cynthia ricini Peer-reviewed

    Shinpei Kawaoka, Susumu Katsuma, Yan Meng, Nobumitsu Hayashi, Kazuei Mita, Toru Shimada

    GENE　431　(1-2)　33-38　2009/02

    DOI： 10.1016/j.gene.2008.11.004 　

    ISSN： 0378-1119

  33. The genome of a lepidopteran model insect, the silkworm Bombyx mori Peer-reviewed

    Qingyou Xia, Jun Wang, Zeyang Zhou, Ruiqiang Li, Wei Fan, Daojun Cheng, Tingcai Cheng, Junji Qin, Jun Duan, Hanfu Xu, Qibin Li, Ning Li, Mingwei Wang, Fangyin Dai, Chun Liu, Ying Lin, Ping Zhao, Huijie Zhang, Shiping Liu, Xingfu Zha, Chunfeng Li, Aichun Zhao, Minhui Pan, Guoqing Pan, Yihong Shen, Zhihong Gao, Zilong Wang, Genhong Wang, Zhengli Wu, Yong Hou, Chunli Chai, Quanyou Yu, Ningjia He, Ze Zhang, Songgang Li, Huanming Yang, Cheng Lu, Jian Wang, Zhonghuai Xiang, Masahiro Kasahara, Yoichiro Nakatani, Kimiko Yamamoto, Hiroaki Abe, Brudrul Ahsan, Takaaki Daimon, Koichiro Doi, Tsuguru Fujii, Haruhiko Fujiwara, Asao Fujiyama, Ryo Futahashi, Shin Ichi Hashimoto, Jun Ishibashi, Masafumi Iwami, Keiko Kadono-Okuda, Hiroyuki Kanamori, Hiroshi Kataoka, Susumu Katsuma, Shinpei Kawaoka, Hideki Kawasaki, Yuji Kohara, Toshinori Kozaki, Reginaldo M. Kuroshu, Seigo Kuwazaki, Kouji Matsushima, Hiroshi Minami, Yukinobu Nagayasu, Tatsuro Nakagawa, Junko Narukawa, Junko Nohata, Kazuko Ohishi, Yukiteru Onor, Mizuko Osanai-Futahashi, Katsuhisa Ozaki, Wei Qu, Ladislav Roller, Shin Sasaki, Takuji Sasaki, Atsushi Seino, Masaru Shimomura, Michihiko Shimomura, Tadasu Shini, Tetsuro Shinoda, Takahiro Shiotsuki, Yoshitaka Suetsugu, Sumio Sugano, Makiko Suwa, Yutaka Suzuki, Shigeharu Takiya, Toshiki Tamura, Hiromitsu Tanaka, Yoshiaki Tanaka, Kazushige Touhara, Tomoyuki Yamada, Minoru Yamakawa, Naoki Yamanaka, Hiroshi Yoshikawa, Yang Sheng Zhong, Toru Shimada, Shinichi Morishita

    Insect Biochemistry and Molecular Biology　38　(12)　1036-1045　2008/12

    DOI： 10.1016/j.ibmb.2008.11.004 　

    ISSN： 0965-1748

  34. Bombyx small RNAs: Genomic defense system against transposons in the silkworm, Bombyx mori Peer-reviewed

    Shinpei Kawaoka, Nobumitsu Hayashia, Susumu Katsuma, Hirohisa Kishino, Yuji Kohara, Kazuei Mita, Toru Shimada

    INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY　38　(12)　1058-1065　2008/12

    DOI： 10.1016/j.ibmb.2008.03.007 　

    ISSN： 0965-1748

  35. Bombyx mori nucleopolyhedrovirus SNF2 global transactivator homologue (Bm33) enhances viral pathogenicity in B. mori larvae Peer-reviewed

    Susumu Katsuma, Tsuguru Fujii, Shinpei Kawaoka, Toru Shimada

    JOURNAL OF GENERAL VIROLOGY　89　3039-3046　2008/12

    DOI： 10.1099/vir.0.2008/004887-0 　

    ISSN： 0022-1317

  36. Genome-wide survey for baculoviral host homologs using the Bombyx genome sequence Peer-reviewed

    Susumu Katsuma, Shinpei Kawaoka, Kazuei Mita, Toru Shimada

    INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY　38　(12)　1080-1086　2008/12

    DOI： 10.1016/j.ibmb.2008.05.008 　

    ISSN： 0965-1748

  37. Developmentally synchronized expression of two Bombyx mori Piwi subfamily genes, SIWI and BmAGO3 in germ-line cells Peer-reviewed

    Shinpei Kawaoka, Kosuke Minami, Susumu Katsuma, Kazuei Mita, Toru Shimada

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　367　(4)　755-760　2008/03

    DOI： 10.1016/j.bbrc.2008.01.013 　

    ISSN： 0006-291X

  38. Functional analysis of four Gloverin-like genes in the silkworm, Bombyx mori Peer-reviewed

    Shinpei Kawaoka, Susumu Katsuma, Takaaki Daimon, Ryoko Isono, Naoko Omuro, Kazuei Mita, Toru Shimada

    ARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY　67　(2)　87-96　2008/02

    DOI： 10.1002/arch.20223 　

    ISSN： 0739-4462

  39. Prominent down-regulation of storage protein genes after bacterial challenge in eri-silkworm, Samia cynthia ricini Peer-reviewed

    Yan Meng, Naoko Omuro, Shunsuke Funaguma, Takaaki Daimon, Shinpei Kawaoka, Susumu Katsuma, Toru Shimada

    ARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY　67　(1)　9-19　2008/01

    DOI： 10.1002/arch.20214 　

    ISSN： 0739-4462

    eISSN： 1520-6327

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Misc. 18

  1. W染色体由来の雌特異的piRNAがカイコの性を決定する

    古賀光, 木内隆史, 川本宗孝, 庄司佳祐, 新井祐二, 河岡慎平, 菅野純夫, 鈴木穣, 嶋田透, 勝間進

    日本蚕糸学会大会・蚕糸・昆虫機能学術講演会講演要旨集　84th　28　2014/03/09

  2. BmHP1aは高発現な遺伝子の転写開始点近傍に結合し,それらの遺伝子発現を正に制御する

    庄司佳祐, 原加保里, 川本宗孝, 河岡慎平, 菅野純夫, 木内隆史, 嶋田透, 鈴木穣, 勝間進

    日本蚕糸学会大会・蚕糸・昆虫機能学術講演会講演要旨集　84th　30　2014/03/09

  3. トランスクリプトーム解析によるカイコの性決定・性分化メカニズムの解明

    古賀光, 木内隆史, 川本宗孝, 庄司佳祐, 新井祐二, 河岡慎平, 菅野純夫, 鈴木穣, 嶋田透, 勝間進

    日本蚕糸学会大会・蚕糸・昆虫機能学術講演会講演要旨集　83rd　27　2013/03/18

  4. バキュロウイルスの宿主行動操作に関与する宿主遺伝子の探索

    國生龍平, 木内隆史, 河岡慎平, 川本宗孝, 鈴木穣, 菅野純夫, 嶋田透, 勝間進

    日本蚕糸学会大会・蚕糸・昆虫機能学術講演会講演要旨集　83rd　73　2013/03/18

  5. カイコにおけるHP1ファミリータンパク質の役割

    庄司佳祐, 原加保里, 河岡慎平, 菅野純夫, 木内隆史, 嶋田透, 鈴木穣, 勝間進

    日本蚕糸学会大会・蚕糸・昆虫機能学術講演会講演要旨集　83rd　25　2013/03/18

  6. カイコHP1aタンパク質と遺伝子発現との関係

    庄司佳祐, 原加保里, 川本宗孝, 河岡慎平, 菅野純夫, 木内隆史, 嶋田透, 鈴木穣, 勝間進

    日本分子生物学会年会プログラム・要旨集(Web)　36th　WEB ONLY 3P-0259　2013

  7. 形質転換BmN4細胞における外来遺伝子発現抑制メカニズム

    光武宏, 河岡慎平, 木内隆史, 小林真希, 吉川真由, 鈴木穣, 菅野純夫, 嶋田透, 泊幸秀, 勝間進, 小林淳

    日本蚕糸学会大会・蚕糸・昆虫機能学術講演会講演要旨集　82nd　59　2012/03/18

  8. カイコをモデルとしたpiRNA研究

    勝間進, 河岡慎平, 庄司佳祐, 古賀光, 木内隆史, 嶋田透

    日本分子生物学会年会プログラム・要旨集(Web)　35th　WEB ONLY 2W1II-2　2012

  9. カイコpiRNA経路におけるHP1ファミリータンパク質の役割

    庄司佳祐, 原加保里, 河岡慎平, 菅野純夫, 木内隆史, 嶋田透, 鈴木穣, 勝間進

    日本分子生物学会年会プログラム・要旨集(Web)　35th　WEB ONLY 3P-0181　2012

  10. カイコ卵巣と産下卵に由来するpiRNAの比較解析

    新井祐二, 河岡慎平, 鈴木穣, 菅野純夫, 嶋田透, 勝間進

    日本蚕糸学会大会・蚕糸・昆虫機能学術講演会講演要旨集　81st　26　2011/03/20

  11. Bombyx mori macula‐like virus RNAを利用したpiRNA生合成経路の検討

    木内隆史, 河岡慎平, 原加保里, 鈴木穣, 菅野純夫, 嶋田透, 勝間進

    日本蚕糸学会大会・蚕糸・昆虫機能学術講演会講演要旨集　81st　27　2011/03/20

  12. piRNA経路におけるHeat Shock Protein90(HSP90)の機能

    安原聡, 河岡慎平, 鈴木穣, 菅野純夫, 嶋田透, 勝間進

    日本蚕糸学会大会・蚕糸・昆虫機能学術講演会講演要旨集　81st　27　2011/03/20

  13. KG系統のW染色体が引き起こす雌の雄化とpiRNAとの関係について

    原加保里, 河岡慎平, 藤井告, 鈴木穣, 菅野純夫, 嶋田透, 勝間進

    日本蚕糸学会大会・蚕糸・昆虫機能学術講演会講演要旨集　81st　26　2011/03/20

  14. カイコ光沢不眠蚕遺伝子nm‐gはエクジソン生合成に関わるshort‐chain dehydrogenase/reductaseをコードする

    伊藤克彦, 河岡慎平, 木内信, 藤本善徳, 丹羽隆介, 篠田徹郎, 伴野豊, 嶋田透, 勝間進

    日本応用動物昆虫学会大会講演要旨　54th　63　2010/03/12

  15. カイコW染色体から産生されるpiRNA

    河岡慎平, 門田幸二, 林伸光, 阿部広明, 藤井告, 鈴木穣, 菅野純夫, 嶋田透, 勝間進

    日本蚕糸学会大会・蚕糸・昆虫機能学術講演会講演要旨集　80th　2010

  16. カイコ生殖巣に存在する small RNA の特性と機能

    河岡 慎平, 嶋田 透, 勝間 進

    蚕糸・昆虫バイオテック = Sanshi-konchu biotec　77　(3)　219-225　2008/12/01

    Publisher: 日本蚕糸学会

    DOI： 10.11416/konchubiotec.77.3_219 　

    ISSN： 1881-0551

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    カイコ生殖巣に存在するsmall RNAの特性と機能。多くの生物のゲノム解読が完了した昨今、「ゲノム上に存在するタンパク質非コード領域が持つ機能」は、ますます興味深い問題のひとつである。カイコゲノムのほぼ80％、ヒトゲノムでは実に98％が、反復配列をはじめとするタンパク質非コード領域であると認識されている。長い間、これらの領域は「ジャンクDNA」などと呼ばれ、生物にとって不要なものであると見なされてきた。しかしながら、最近になって、これら非コード領域が活発に転写され、転写された非コードRNAが重要な生物機能を有する、ということが分かってきた。我々が最もよく知っている重要な非コードRNAとしては、tRNAやrRNAが挙げられるが、大きな注目が集まっているのは、長さが21-30塩基程度の小さなRNA、small RNAの機能である。ここでは、動物のsmall RNAの基本的な機能に関して概説するとともに、筆者らが最近得た、カイコにおけるsmall RNA研究についての結果を紹介する。

  17. F223 カイコ生殖巣におけるsilkworm Piwi (SIWI)とBmAGO3の同調的発現

    河岡 慎平, 南 皓輔, 勝間 進, 三田 和英, 嶋田 透

    日本応用動物昆虫学会大会講演要旨　(52)　110-110　2008/03/12

    Publisher: 日本応用動物昆虫学会

  18. B306 カイコにおける抗菌タンパク質の進化 : グロベリンファミリーの構造と機能

    河岡 慎平, 大門 高明, 大室 奈緒子, 磯野 涼子, 三田 和英, 勝間 進, 嶋田 透

    日本応用動物昆虫学会大会講演要旨　(51)　31-31　2007/03/01

    Publisher: 日本応用動物昆虫学会

Show all ︎Show first 5

Research Projects 13

  1. 呼吸困難質的プロファイルマルチオミクス解析による包括的呼吸リハビリテーション開発

    海老原 覚, 河岡 慎平

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(B)

    Institution: 東北大学

    2024/04/01 - 2029/03/31

  2. がん悪液質に随伴する好中球サブセットの実態解明と創薬標的探索

    河岡 慎平

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 挑戦的研究(開拓)

    Institution: 東北大学

    2025/06/27 - 2028/03/31

  3. がん悪液質における好中球の病態機能解明とケミカルプロテオミクスによる創薬標的探索

    河岡 慎平

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 国際共同研究加速基金(海外連携研究)

    Institution: 東北大学

    2024/09/09 - 2027/03/31

  4. がんによる全身的な宿主免疫抑制の理解に基づくがん免疫療法の発展

    河岡 慎平

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(B)

    Institution: 東北大学

    2024/04/01 - 2027/03/31

  5. がんに起因する宿主の多細胞連関の異常に関する統合的研究

    河岡 慎平

    Offer Organization: 科学技術振興機構

    System: 戦略的な研究開発の推進 創発的研究支援事業

    Institution: 京都大学

    2021 - 2027

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    本研究では、がんによって個体に不調が生じるのはなぜか、という根本的な問題に、「がんに起因する宿主の多細胞連関の異常」という新しい視点でとりくみます。がんを根治できない場合、がんに起因する身体の不調を抑え込むことが重要です。そのためには、がんによって不調が生じるしくみを理解する必要があります。本研究を進展させ、がんを消せなくても健康長寿を全うできるような世の中を実現する一助になりたいと考えています。

  6. がんに起因する多臓器の代謝異常を制御する新しい宿主因子の病態機能解析

    河岡 慎平

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(B)

    Category: 基盤研究(B)

    Institution: 京都大学

    2020/04/01 - 2024/03/31

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    根治不能となってしまったがんは、宿主個体にさまざまな悪影響をもたらす。たとえば、脂肪や筋肉、体重の減少、食欲の減退、慢性炎症などを具体例として挙げることができる。これらの症状は臨床的にはがん悪液質として知られ、がん患者のQOLや治療効率を低下させるとともに、医療費を増大させるなど、重要なアンメットニーズであるといえる。 <BR> 現時点はがんに起因する宿主の病態・不調を強力に緩和できる方法は存在しない。病態が多臓器・多因子性であり、どの病態が不調に直結しているのか、どの悪影響を抑制すべきなのかを考えることが難しいことがその一因であると考えられる。 <BR> 研究代表者は、マウスがんモデルとマルチオミクス解析を活用することで、がんが個体に与える影響をできる限り包括的に理解し、また、各々の影響に関わる宿主側の要因を同定しようとしている。本年度も、この発想に基づく研究を推進した。その結果、がんが、宿主の肝臓にさまざまな代謝異常を引き起こしていることがわかった。たとえば、ウレア回路が抑制されていた。ウレア回路は、タンパク質分解などで生じた有毒なアンモニアを無毒なウレアへと変換して大概に排出するために必須の、極めて需要な代謝回路である。がんをもつ個体の肝臓ではウレア回路を構成する代謝物や遺伝子の発現量が変化しており、また、血液中のウレアの量が減少していた。代表者は、この異常に関わる新しい宿主因子を同定し、また、本因子がウレア回路の異常にどのように関わるのかというメカニズムの一部を明らかにした。本研究については論文のリバイズ版を投稿済みである。また、本年度は、上記宿主因子が関与しない異常並びにそれらの異常に関わる別の宿主因子に関する手がかりを得ることもできた。この戦略によってがん悪液質という複雑な現象を丁寧に切り分けていきたい。

  7. がんに起因する多臓器代謝異常に対する宿主アダプテーションのトランスオミクス解析

    河岡 慎平

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 新学術領域研究(研究領域提案型)

    Category: 新学術領域研究(研究領域提案型)

    Institution: 京都大学

    2020/04/01 - 2022/03/31

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    根治不能となってしまったがんは、やがて、宿主個体にさまざまな悪影響を及ぼす。たとえば、筋肉・脂肪・体重の減少、食欲の低下、肝臓の代謝異常、免疫系の変容などを例として挙げることができる。その一方で、がんが根治不能であるからといって、個体がすぐに死に至るわけではない。このことは、がんをもつ個体が、がんによって生じる変容にアダプテーションしている可能性を示している。つまり、がんをもつ個体において観察される変容は、がんによって生じている不調である可能性と、がんに対する宿主のアダプテーションである可能性がある。本研究では、新学術領域「代謝アダプテーション」の一員として、がんによって生じる代謝異常に対して個体がどのようにアダプテーションするのかを明らかにしようとした。 <BR> 本研究では、がんをもつ個体で観察される変容 (がんを持たない個体との違い) を、宿主の異常・撹乱とアダプテーションとして切り分けることを試みた。具体的には、がんをもつ個体の宿主臓器の状態をマルチオミクスによって記載する。各々の変容に重要でありうる宿主因子を絞り込み、これを欠失あるいは過剰発現させる。その上で改めてがんを発生させ、がんによる変容及び個体の不調が緩和あるは増悪するかを調べた。 <BR> その結果、肝臓や脂肪といった複数の臓器において、がんによる撹乱とアダプテーションを切り分けること、また、撹乱・アダプテーションに重要な宿主因子を複数同定することができた。得られた成果は論文として投稿済みである。本研究により、がんによる撹乱と宿主のアダプテーションのせめぎ合いの一端が明らかとなった。本研究で確立したアプローチを発展させ、がんに起因する個体の不調という複雑な現象を一つ一つ丁寧に切り分けていきたいと考えている。

  8. Functional analysis of host genes that mediate cancer cachexia

    Kawaoka Shinpei

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Early-Career Scientists

    Category: Grant-in-Aid for Early-Career Scientists

    Institution: Kyoto University

    2018/04/01 - 2021/03/31

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    Despite advances in cancer therapeutics, more than 370,000 people die due to cancers per year in Japan. In other words, more than 370,000 people are forced to live with incurable cancers. Such incurable cancers adversely affect the host in various manners. For example, patients with incurable cancers show reduced appetite, weight loss, impaired therapeutic efficacy, and so on. These symptoms are clinically known as cancer cachexia. Yet, no effective therapeutics on cancer cachexia have been available to date. This study reveals a novel host factor that mediates abnormalities in the adipose tissues in cancer cachexia.

  9. Transomics analyses on metabolic adaptation against cancer cachexia

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: Kyoto University

    2018/04/01 - 2020/03/31

  10. エンハンサーRNAの体系的分類と作動原理に関する統合的研究

    河岡 慎平

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 新学術領域研究(研究領域提案型)

    Category: 新学術領域研究(研究領域提案型)

    Institution: 株式会社国際電気通信基礎技術研究所

    2015/04/01 - 2017/03/31

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    エンハンサーは、標的である遺伝子がいつ・どこで・どのくらい発現するかを決める重要な非コードゲノム領域である。エンハンサーRNAはエンハンサーから発現する非コードRNAである。エンハンサーRNAの機能的重要性に関しては、分野内でも意見が分かれており、エンハンサー機能に必須である、という説から、エンハンサーとプロモーターが相互作用する際に転写される副産物にすぎない、という説まで、様々である。本研究では、急性リンパ性白血病の細胞株ならびにマウスを用いて、１.エンハンサーRNAの大規模配列決定ならびにバイオインフォマティクス解析と、２.エンハンサー領域全体ならびにエンハンサーRNA該当領域のノックアウト作成に基づくエンハンサーゲノム領域の機能評価を行った。 <BR> １.では、急性リンパ性白血病細胞を薬剤処理した際に観察されるゲノムワイドな遺伝子発現変化と、エンハンサーRNAの発現量変動に相関があるかどうかを調べた。その結果、エンハンサーによっては、エンハンサーRNAと標的遺伝子発現の間に正の相関が認められたが、ゲノムワイドに見ると相関の度合いは弱いことが判明した。 <BR> ２.では、モデルとして取り扱った細胞死を制御する遺伝子のエンハンサーに関して、重点的なノックアウト解析を行った。エンハンサー領域全体をノックアウトすると当該細胞死遺伝子の発現制御に異常をきたすことから、エンハンサー領域全体の重要性は担保された。しかしながら、エンハンサーRNAの個別のノックアウトでは、顕著な表現型は観察されなかった。本研究は、エンハンサーRNAの機能的重要性に重要な示唆を与えるものである。

  11. Inverse analysis of transcription elongation process using Bayesian Inference

    Yoshida Ryo, KAWAOKA SHINPEI, SHINSUKE KOYAMA

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: The Institute of Statistical Mathematics

    2015/04/01 - 2017/03/31

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    Combining data science technologies and a widely used RNA sequencing technique called Total RNA-seq, we aimed to inversely predict a highly complex process of transcription elongation through which RNA polymerase II traverses the DNA template strand. Recently several experimental technologies, for instance, GRO-seq and NET-seq, have been developed for the genome-wide measurement of transcription elongation rates. However, such methods have not widely spread so far because of their experimental difficulties. Our study has shown that using the well-established RNA sequencing method coupled with a simple data science algorithm enables us to reconstruct the transcription elongation process by solving the inverse problem. This has opened a new possibility for transcription elongation studies.

  12. 遠位エンハンサーの標的遺伝子探索原理に関する研究

    河岡 慎平

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 研究活動スタート支援

    Category: 研究活動スタート支援

    Institution: 株式会社国際電気通信基礎技術研究所

    2014/08/29 - 2015/03/31

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    エンハンサーは、標的とする遺伝子の時空間発現パターンを決定づける重要なゲノム領域である。エンハンサーは時には数 Mb 離れたところ に存在する標的遺伝子の発現を制御する。遠位にあるエンハンサーがどのように標的遺伝子を見つけるかという問題は未解決であり、 エンハンサーの標的を正確に予測することは困難である。本研究では、エンハンサーがどのように遠位に存在する標的遺伝子を見つけるのか、という問題を解決するために、細胞死に関わるエンハンサーをモデルとした新規の実験系構築を行った。 まず、公共のデータベースを利用して、細胞死に関与しうるエンハンサーの同定を行った。その結果、いくつかの細胞系譜において、細胞死に関与しうるエンハンサーを発見した。そのうち、血球細胞の細胞死に関与しうるエンハンサーを対象とした解析に注力した。 次に、当該血球細胞におけるエンハンサーのゲノム編集実験、あるいは転写活性化因子のテザリング実験を実現するために、当該細胞に対するトランスフェクション効率の検討を行った。リポフェクション、エレクトロポレーションなどのいくつかの実験系を検討した結果、エレクトロポレーションによる実験系の効率がもっとも良いことが分かった。 <br> 以上確立した実験系を利用して、同定したエンハンサーに対するゲノム編集実験を行った。その結果、エンハンサーの配列あるいは活性の改変を行うためのいくつかのプロトコルを確立することに成功した。今後は、当該年度に確立した実験系を活用して、エンハンサーに関する解析を進めていく予定である。

  13. piRNAの機能解析に基づくカイコ性決定・胚休眠機構の解明

    河岡 慎平

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特別研究員奨励費

    Category: 特別研究員奨励費

    Institution: 東京大学

    2009 - 2011

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    カイコの性は、雌特具的な性染色体であるW染色体によって強力にコントロールされており、W染色体が1コピーあれば雌性が決定される。このことから、W染色体には強力な雌決定因子がコードされていると考えられてきた。しかしながらごく最近まで、W染色体に由来するタンパク質コード遺伝子はおろか、転写物さえ同定されていなかった。その理由として、W染色体が高密度のトランスポゾン配列群によって占拠されている、ということが挙げられる。このことにより、W染色体の高解像度一次配列を得ることは不可能であると考えられている。 これまでに行った研究では、W染色体に含まれるトランスポゾンの組成をpiRNAの発現解析データをベースにして予測する、という手法を考案し、各種W染色体変異体の解析を併用することにより、性決定領域に近い領域に座乗するトランスポゾン群ならびに、それらに由来するpiRNAを同定することに成功した。本年度はまず、これまでに得られた知見を論文発表することをめざし、"The silkworm W chromosome is a source of female-enriched piRNAs"をRNA誌に発表することができた。本年度は、W染色体に由来するpiRNAと性との関係を調べるべく、カイコ新規変異体KGの解析を行った。KG系統は2010年に藤井らによって単離された系統である。KG系統の雌は部分的に雄化することが知られており、KG系統の変異はW染色体にマップされている。私は、このKG系統が、W染色体とpiRNA、そして性との関係を調べるための格好の材料であると考え、その性状を調査した。Doublesex(dsx)遺伝子は進化的に保存された性分化に関与する転写因子であり、dsxmRNAは性特異的なスプライシングを受ける。興味深いことに、KG雌の卵巣においては、雄型と雌型両方のdsxmRNAが発現していることが判明した。また、KG雌の卵巣においては、精巣特異的であることが知られている複数の遺伝子が異常に発現していることが分かった。すなわち、KG-W染色体変異によって、dsxのスプライシングパターンに異常が生じ、卵巣において部分的な精巣特異的トランスクリプトームが観察されると考えられた。私のこれまでの研究により、w染色体がpiRNAの源であることが分かっている。つぎに、KG-W染色体変異がpiRNAの性状に与える影響を調査した。次世代シーケンサとインフォマティクスを駆使した解析の結果、性決定領域付近に由来するpiRNAの一部の発現がKG系統の卵巣で有意に減少していることが判明した。したがって、KG-W染色体変異は、piRNAの組成に影響するものと考えられた。最後に、KG雌卵巣におけるトランスポゾンの発現を調査した。すると、KG雌卵巣では、多くのトランスポゾンが過剰発現していることが明らかとなった。本研究は、"Altered expression of testis specific genes, piRNAs, and transposons in the silkworm ovary masculinized by a W chromosome mutation'"として、BMCGenomics誌に発表した。

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