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写真a

 
Keiko Horiuchi
 
Organization
Graduate School of Medicine Department of Medicine Molecular Biology Assistant Professor
School of Medicine Medical Course
Title
Assistant Professor
Homepage
http://dppir.com/
External link

Degree

  • Ph.D. ( The University of Tokyo )

Research Areas

  • Life Science / Molecular biology  / RNA splicing, U12 intron, m6A, WTAP, ZRSR1, ZRSR2, myelodysplastic syndrome, Proteomics

Education

  • The University of Tokyo

    2002.10 - 2005.9

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  • The University of Tokyo

    1998.4 - 2002.3

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  • 東京大学理科II類

    1996.4 - 1998.3

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Research History

  • Yokohama City University   School of Medicine Medical Course Molecular Biology   Assistant Professor

    2021.8

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  • Nippon Medical School   Researcher

    2021.4 - 2021.7

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  • Nippon Medical School Institute for Advanced Medical Sciences   Assistant professor

    2018.4 - 2021.3

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  • The University of Tokyo   Assistant Professor

    2014.7 - 2018.3

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  • Center for Genomic Regulaton, Barcelona, Spain

    2014.4 - 2017.9

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  • 東京大学先端科学技術研究センター   計量生物医学研究室   特任助教

    2013.4 - 2014.6

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  • 東京大学先端科学技術研究センター   分子生物医学研究室   特任助教

    2007.4 - 2013.3

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  • The University of Tokyo

    2005.9 - 2007.3

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Papers

  • Multi-omics analysis using antibody-based in situ biotinylation technique suggests the mechanism of Cajal body formation

    Keisuke Noguchi, Hidefumi Suzuki, Ryota Abe, Keiko Horiuchi, Rena Onoguchi-Mizutani, Nobuyoshi Akimitsu, Shintaro Ogawa, Tomohiko Akiyama, Yoko Ike, Yoko Ino, Yayoi Kimura, Akihide Ryo, Hiroshi Doi, Fumiaki Tanaka, Yutaka Suzuki, Atsushi Toyoda, Yuki Yamaguchi, Hidehisa Takahashi

    Cell Reports   43 ( 9 )   2024.9

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    Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.celrep.2024.114734

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  • Chimera RNA transcribed from integrated HPV18 genome with adjacent host genomic region promotes oncogenic gene expression through condensate formation. Reviewed International journal

    Kazuki Furugori, Hidefumi Suzuki, Ryota Abe, Keiko Horiuchi, Tomohiko Akiyama, Tomonori Hirose, Atsushi Toyoda, Hidehisa Takahashi

    Genes to cells : devoted to molecular & cellular mechanisms   2024.5

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

    Most cervical cancers are caused by human papillomavirus (HPV) infection. In HeLa cells, the HPV18 viral genome is integrated at chromosome 8q24.21 and activates transcription of the proto-oncogene c-Myc. However, the mechanism of how the integrated HPV genome and its transcribed RNAs exhibit transcription activation function has not been fully elucidated. In this study, we found that HPV18 transcripts contain an enhancer RNA-like function to activate proximal genes including CCAT1-5L and c-Myc. We showed that the human genome-integrated HPV18 genes are activated by transcription coregulators including BRD4 and Mediator. The transcribed HPV18 RNAs form a liquid-like condensate at chromosome 8q24.21 locus, which in turn accumulates RNA polymerase II. Moreover, we focused on a relatively uncharacterized transcript from the upstream region of CCAT1, named URC. The URC RNA is transcribed as a chimera RNA with HPV18 and is composed of the 3'-untranslated region of the HPV18 transcript. We experimentally showed that the URC contributes to stabilization of HPV18 RNAs by supplying a polyadenylation site for the HPV18 transcript. Our findings suggest that integrated HPV18 at 8q24.21 locus produces HPV18-URC chimera RNA and promotes tumorigenesis through RNA-based condensate formation.

    DOI： 10.1111/gtc.13121

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  • MED26-containing Mediator may orchestrate multiple transcription processes through organization of nuclear bodies. International journal

    Hidefumi Suzuki, Kazuki Furugori, Ryota Abe, Shintaro Ogawa, Sayaka Ito, Tomohiko Akiyama, Keiko Horiuchi, Hidehisa Takahashi

    BioEssays : news and reviews in molecular, cellular and developmental biology   e2200178   2023.2

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    Mediator is a coregulatory complex that plays essential roles in multiple processes of transcription regulation. One of the human Mediator subunits, MED26, has a role in recruitment of the super elongation complex (SEC) to polyadenylated genes and little elongation complex (LEC) to non-polyadenylated genes, including small nuclear RNAs (snRNAs) and replication-dependent histone (RDH) genes. MED26-containing Mediator plays a role in 3' Pol II pausing at the proximal region of transcript end sites in RDH genes through recruitment of Cajal bodies (CBs) to histone locus bodies (HLBs). This finding suggests that Mediator is involved in the association of CBs with HLBs to facilitate 3' Pol II pausing and subsequent 3'-end processing by supplying 3'-end processing factors from CBs. Thus, we argue the possibility that Mediator is involved in the organization of nuclear bodies to orchestrate multiple processes of gene transcription.

    DOI： 10.1002/bies.202200178

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  • Zrsr2 and functional U12-dependent spliceosome are necessary for follicular development. International journal

    Isabel Gómez-Redondo, Eva Pericuesta, Paula Navarrete-Lopez, Priscila Ramos-Ibeas, Benjamín Planells, Noelia Fonseca-Balvís, Aida Vaquero-Rey, Raúl Fernández-González, Ricardo Laguna-Barraza, Keiko Horiuchi, Alfonso Gutiérrez-Adán

    iScience   25 ( 2 )   103860 - 103860   2022.2

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

    ZRSR2 is a splicing factor involved in recognition of 3'-intron splice sites that is frequently mutated in myeloid malignancies and several tumors; however, the role of mutations of Zrsr2 in other tissues has not been analyzed. To explore the biological role of ZRSR2, we generated three Zrsr2 mutant mouse lines. All Zrsr2 mutant lines exhibited blood cell anomalies, and in two lines, oogenesis was blocked at the secondary follicle stage. RNA-seq of Zrsr2 mu secondary follicles showed aberrations in gene expression and showed altered alternative splicing (AS) events involving enrichment of U12-type intron retention (IR), supporting the functional Zrsr2 action in minor spliceosomes. IR events were preferentially associated with centriole replication, protein phosphorylation, and DNA damage checkpoint. Notably, we found alterations in AS events of 50 meiotic genes. These results indicate that ZRSR2 mutations alter splicing mainly in U12-type introns, which may affect peripheral blood cells, and impede oogenesis and female fertility.

    DOI： 10.1016/j.isci.2022.103860

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  • Wilms' Tumor 1-Associating Protein complex regulates alternative splicing and polyadenylation at potential G-quadruplex-forming splice site sequences. International journal

    Keiko Horiuchi, Takeshi Kawamura, Takao Hamakubo

    The Journal of biological chemistry   101248 - 101248   2021.9

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

    Wilms' tumor 1-associating protein (WTAP) is a core component of the N6-methyladenosine (m6A)-methyltransferase complex, along with VIRMA, CBLL1, ZC3H13 (KIAA0853), RBM15/15B, and METTL3/14, which generate m6A, a key RNA modification that affects various process of RNA metabolism. WTAP also interacts with splicing factors; however, despite strong evidence suggesting a role of Drosophila WTAP homolog fl(2)d in alternative splicing (AS), its role in splicing regulation in mammalian cells remains elusive. Here we demonstrate using RNAi coupled with RNA-seq that WTAP, VIRMA, CBLL1, and ZC3H13 modulate AS, promoting exon skipping and intron retention in AS events that involve short introns/exons with higher GC content and introns with weaker polypyrimidine-tract and branch points. Further analysis of GC-rich sequences involved in AS events regulated by WTAP, together with minigene assay analysis, revealed potential G-quadruplex formation at splice sites where WTAP has an inhibitory effect. We also found that several AS events occur in the last exon of one isoform of MSL1 and WTAP, leading to competition for polyadenylation. Proteomic analysis also suggested that WTAP/CBLL1 interaction promotes recruitment of the 3'-end processing complex. Taken together, our results indicate that the WTAP complex regulates AS and alternative polyadenylation via inhibitory mechanisms in GC-rich sequences.

    DOI： 10.1016/j.jbc.2021.101248

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  • Frequent Germline and Somatic Single Nucleotide Variants in the Promoter Region of the Ribosomal RNA Gene in Japanese Lung Adenocarcinoma Patients. International journal

    Riuko Ohashi, Hajime Umezu, Ayako Sato, Tatsuya Abé, Shuhei Kondo, Kenji Daigo, Seijiro Sato, Norikazu Hara, Akinori Miyashita, Takeshi Ikeuchi, Teiichi Motoyama, Masashi Kishi, Tadahiro Nagaoka, Keiko Horiuchi, Atsushi Shiga, Shujiro Okuda, Tomoki Sekiya, Aya Ohtsubo, Kosuke Ichikawa, Hiroshi Kagamu, Toshiaki Kikuchi, Satoshi Watanabe, Jun-Ichi Tanuma, Peter Schraml, Takao Hamakubo, Masanori Tsuchida, Yoichi Ajioka

    Cells   9 ( 11 )   2020.11

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

    Ribosomal RNA (rRNA), the most abundant non-coding RNA species, is a major component of the ribosome. Impaired ribosome biogenesis causes the dysfunction of protein synthesis and diseases called "ribosomopathies," including genetic disorders with cancer risk. However, the potential role of rRNA gene (rDNA) alterations in cancer is unknown. We investigated germline and somatic single-nucleotide variants (SNVs) in the rDNA promoter region (positions -248 to +100, relative to the transcription start site) in 82 lung adenocarcinomas (LUAC). Twenty-nine tumors (35.4%) carried germline SNVs, and eight tumors (9.8%) harbored somatic SNVs. Interestingly, the presence of germline SNVs between positions +1 and +100 (n = 12; 14.6%) was associated with significantly shorter recurrence-free survival (RFS) and overall survival (OS) by univariate analysis (p < 0.05, respectively), and was an independent prognostic factor for RFS and OS by multivariate analysis. LUAC cell line PC9, carrying rDNA promoter SNV at position +49, showed significantly higher ribosome biogenesis than H1650 cells without SNV. Upon nucleolar stress induced by actinomycin D, PC9 retained significantly higher ribosome biogenesis than H1650. These results highlight the possible functional role of SNVs at specific sites of the rDNA promoter region in ribosome biogenesis, the progression of LUAC, and their potential prognostic value.

    DOI： 10.3390/cells9112409

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  • Sex-Dimorphic Behavioral Alterations and Altered Neurogenesis in U12 Intron Splicing-Defective <i>Zrsr1</i> Mutant Mice. Reviewed

    Alén F, Gómez-Redondo I, Rivera P, Suárez J, Ramos-Ibeas P, Pericuesta E, Fernández-González R, Perez-Cerezales S, Horiuchi K, Orio L, Rodriguez de, Fonseca F, Gutiérrez-Adán A

    International journal of molecular sciences   20 ( 14 )   2019.7

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  • The RNA Methyltransferase Complex of WTAP, METTL3, and METTL14 Regulates Mitotic Clonal Expansion in Adipogenesis. Reviewed International journal

    Masatoshi Kobayashi, Mitsuru Ohsugi, Takayoshi Sasako, Motoharu Awazawa, Toshihiro Umehara, Aya Iwane, Naoki Kobayashi, Yukiko Okazaki, Naoto Kubota, Ryo Suzuki, Hironori Waki, Keiko Horiuchi, Takao Hamakubo, Tatsuhiko Kodama, Seiichiro Aoe, Kazuyuki Tobe, Takashi Kadowaki, Kohjiro Ueki

    Molecular and cellular biology   38 ( 16 )   2018.8

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    Adipocyte differentiation is regulated by various mechanisms, of which mitotic clonal expansion (MCE) is a key step. Although this process is known to be regulated by cell cycle modulators, the precise mechanism remains unclear. N6-Methyladenosine (m6A) posttranscriptional RNA modification, whose methylation and demethylation are performed by respective enzyme molecules, has recently been suggested to be involved in the regulation of adipogenesis. Here, we show that an RNA N6-adenosine methyltransferase complex consisting of Wilms' tumor 1-associating protein (WTAP), methyltransferase like 3 (METTL3), and METTL14 positively controls adipogenesis by promoting cell cycle transition in MCE during adipogenesis. WTAP, coupled with METTL3 and METTL14, is increased and distributed in nucleus by the induction of adipogenesis dependently on RNA in vitro Knockdown of each of these three proteins leads to cell cycle arrest and impaired adipogenesis associated with suppression of cyclin A2 upregulation during MCE, whose knockdown also impairs adipogenesis. Consistent with this, Wtap heterozygous knockout mice are protected from diet-induced obesity with smaller size and number of adipocytes, leading to improved insulin sensitivity. These data provide a mechanism for adipogenesis through the WTAP-METTL3-METTL14 complex and a potential strategy for treatment of obesity and associated disorders.

    DOI： 10.1128/MCB.00116-18

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  • Impaired Spermatogenesis, Muscle, and Erythrocyte Function in U12 Intron Splicing-Defective Zrsr1 Mutant Mice Reviewed

    Keiko Horiuchi, Serafín Perez-Cerezales, Panagiotis Papasaikas, Priscila Ramos-Ibeas, Angela Patricia López-Cardona, Ricardo Laguna-Barraza, Noelia Fonseca Balvís, Eva Pericuesta, Raul Fernández-González, Benjamín Planells, Alberto Viera, Jose Angel Suja, Pablo Juan Ross, Francisco Alén, Laura Orio, Fernando Rodriguez de Fonseca, Belén Pintado, Juan Valcárcel, Alfonso Gutiérrez-Adán

    Cell Reports   23 ( 1 )   143 - 155   2018.4

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

    DOI： 10.1016/j.celrep.2018.03.028

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  • Suppression of Slit2/Robo1 mediated HUVEC migration by Robo4 Reviewed

    Satoshi Enomoto, Kenichi Mitsui, Takeshi Kawamura, Hiroko Iwanari, Kenji Daigo, Keiko Horiuchi, Takashi Minami, Tatsuhiko Kodama, Takao Hamakubo

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   469 ( 4 )   797 - 802   2016.1

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

    DOI： 10.1016/j.bbrc.2015.12.075

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  • Identification of Wilms' Tumor 1-associating Protein Complex and Its Role in Alternative Splicing and the Cell Cycle Reviewed

    Keiko Horiuchi, Takeshi Kawamura, Hiroko Iwanari, Riuko Ohashi, Makoto Naito, Tatsuhiko Kodama, Takao Hamakubo

    JOURNAL OF BIOLOGICAL CHEMISTRY   288 ( 46 )   33292 - 33302   2013.11

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

    DOI： 10.1074/jbc.M113.500397

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  • Wilms tumor 1-associating protein regulates G(2)/M transition through stabilization of cyclin A2 mRNA Reviewed

    Keiko Horiuchi, Michihisa Umetani, Takashi Minami, Hiroto Okayama, Shinji Takada, Masayuki Yamamoto, Hiroyuki Aburatani, Patrick C. Reid, David E. Housman, Takao Hamakubo, Tatsuhiko Kodama

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   103 ( 46 )   17278 - 17283   2006.11

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

    DOI： 10.1073/pnas.0608357103

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  • Histopathological studies of aortic dissection in streptozotocin-induced diabetic APA hamsters Reviewed

    K Horiuchi, A Takatori, T Inenaga, E Ohta, Y Ishii, S Kyuwa, Y Yoshikawa

    EXPERIMENTAL ANIMALS   54 ( 4 )   363 - 367   2005.7

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

    DOI： 10.1538/expanim.54.363

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  • Vascular endothelial growth factor-and thrombin-induced termination factor, down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis Reviewed

    T Minami, K Horiuchi, M Miura, MR Abid, W Takabe, N Noguchi, T Kohro, XJ Ge, H Aburatani, T Hamakubo, T Kodama, WC Aird

    JOURNAL OF BIOLOGICAL CHEMISTRY   279 ( 48 )   50537 - 50554   2004.11

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

    DOI： 10.1074/jbc.M406454200

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  • Interaction between hex and GATA transcription factors in vascular endothelial cells inhibits flk-1/KDR-mediated vascular endothelial growth factor signaling. Reviewed International journal

    Takashi Minami, Takeshi Murakami, Keiko Horiuchi, Mai Miura, Tamio Noguchi, Jun-ichi Miyazaki, Takao Hamakubo, William C Aird, Tatsuhiko Kodama

    The Journal of biological chemistry   279 ( 20 )   20626 - 35   2004.5

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    Recent evidence supports a role for GATA transcription factors as important signal intermediates in differentiated endothelial cells. The goal of this study was to identify proteins that interact with endothelial-derived GATA transcription factors. Using yeast two-hybrid screening, we identified hematopoietically expressed homeobox (Hex) as a GATA-binding partner in endothelial cells. The physical association between Hex and GATA was confirmed with immunoprecipitation in cultured cells. Hex overexpression resulted in decreased flk-1/KDR expression, both at the level of the promoter and the endogenous gene, and attenuated vascular endothelial growth factor-mediated tube formation in primary endothelial cell cultures. In electrophoretic mobility shift assays, Hex inhibited the binding of GATA-2 to the flk-1/KDR 5'-untranslated region GATA motif. Finally, in RNase protection assays, transforming growth factor beta1, which has been previously shown to decrease flk-1 expression by interfering with GATA binding activity, was shown to increase Hex expression in endothelial cells. Taken together, the present study provides evidence for a novel association between Hex and GATA and suggests that transforming growth factor beta-mediated repression of flk-1/KDR and vascular endothelial growth factor signaling involves the inducible formation of inhibitory Hex-GATA complexes.

    DOI： 10.1074/jbc.M308730200

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  • Protective effects of Probucol treatment on pancreatic beta-cell function of SZ-induced diabetic APA hamsters Reviewed

    A Takatori, E Ohta, T Inenaga, K Horiuchi, Y Ishii, S Itagaki, S Kyuwa, Y Yoshikawa

    EXPERIMENTAL ANIMALS   52 ( 4 )   317 - 327   2003.7

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    DOI： 10.1538/expanim.52.317

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  • The effect of probucol on atherosclerosis in streptozotocin-induced diabetic-hyperlipidemic APA hamsters in different stages of atherosclerosis Reviewed

    K Horiuchi, A Takatori, T Inenaga, E Ohta, J Yamanouchi, S Kawamura, Y Ishii, S Kyuwa, Y Yoshikawa

    EXPERIMENTAL ANIMALS   51 ( 5 )   457 - 464   2002.10

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    DOI： 10.1538/expanim.51.457

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  • Functional and histochemical analysis on pancreatic islets of APA hamsters with SZ-induced hyperglycemia and hyperlipidemia Reviewed

    A Takatori, E Nishida, T Inenaga, K Horiuchi, S Kawamura, S Itagaki, Y Yoshikawa

    EXPERIMENTAL ANIMALS   51 ( 1 )   9 - 17   2002.1

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    DOI： 10.1538/expanim.51.9

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MISC

  • Wilms’tumor1‐associating protein(WTAP)の肥満・糖代謝への関与の検討

    小林正稔, 大杉満, 笹子敬洋, 小林直樹, 岩根亜弥, 粟澤元晴, 岡崎由希子, 堀内恵子, 浜窪隆雄, 児玉龍彦, 戸辺一之, 植木浩二郎, 門脇孝

    糖尿病   55 ( Supplement 1 )   S.188   2012.4

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    Language：Japanese  

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  • Wilms’tumor1‐associating proteinの肥満・糖代謝への関与の検討

    小林正稔, 大杉満, 笹子敬洋, 粟澤元晴, 岡崎由希子, 堀内恵子, 浜窪隆雄, 児玉龍彦, 戸辺一之, 植木浩二郎, 門脇孝

    日本体質医学会雑誌   73 ( 3 )   230   2011.9

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  • Wilms’ tumor1‐associating proteinの肥満・糖代謝への関与の検討

    小林正稔, 大杉満, 笹子敬洋, 堀内恵子, 浜窪隆雄, 戸辺一之, 植木浩二郎, 門脇孝

    肥満研究   17 ( Supplement )   149   2011.9

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  • WTAP複合体の同定および機能解析(The role of WTAP complex on RNA processing and cellcycle regulation)

    堀内 恵子, 川村 猛, 浜窪 隆雄

    日本生化学会大会プログラム・講演要旨集   84回   4P - 0412   2011.9

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  • CDGAPはROBO1と相互作用して血管内皮細胞のSLIT2依存的な遊走に関与する。

    榎本悟士, 川村猛, 岩成宏子, 太期健二, 堀内恵子, 南敬, 児玉龍彦, 浜窪隆雄

    生化学   83回・33回   ROMBUNNO.3P-0186 - 0186   2010.12

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  • RNAプロセッシングおよび細胞周期を制御する新規複合体の機能解析

    堀内恵子, 川村猛, 浜窪隆雄

    生化学   83回・33回   ROMBUNNO.3P-0797 - 0797   2010.12

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  • Roles of Wilms&apos; tumor 1-associating protein (WTAP) in development of obesity and diabetes

    Masatoshi Kobayashi, Mitsuru Ohsugi, Takayoshi Sasako, Naoki Kobayashi, Miho Suzuki, Kazuma Kaneko, Motoharu Awazawa, Yukiko Okazaki, Kohjiro Ueki, Keiko Horiuchi, Takao Hamakubo, Tatsuhiko Kodama, Takashi Kadowaki

    ENDOCRINE JOURNAL   57   S423 - S423   2010.3

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    Language：English   Publishing type：Research paper, summary (international conference)  

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  • 酸化ストレス ストレプトゾトシン誘発高血糖・高脂血症を呈するAPAハムスターすい島におけるプロブコールおよびN-acetyl-L-cysteine投与の影響

    高取敦志, 稲永敏明, 堀内恵子, 石井寿幸, 板垣慎一, 久和茂, 吉川泰弘

    日本糖尿病動物研究会記録   17th   2004

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  • 新規GATA因子結合蛋白質WTAP(Wilms′ tumor 1‐associating protein)の相互作用および細胞内局在

    堀内恵子, 梅渓通久, 南敬, 峯岸直子, 山本雅之, 浜窪隆雄, 児玉龍彦

    日本分子生物学会年会プログラム・講演要旨集   26th   842   2003.11

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  • ストレプトゾトシン誘発高血糖・高脂血症を呈するAPAハムスターすい島におけるプロブコールおよびN-acetyl-L-cysteine投与の影響

    高取敦志, 稲永敏明, 堀内恵子, 石井寿幸, 板垣慎一, 久和茂, 吉川泰弘

    Diabetes Frontier   14 ( 4 )   2003

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  • SZ誘発糖尿病APAハムスターにみられた大動脈解離の病理組織学的検索

    堀内 恵子, 高取 敦志, 稲永 敏明, 太田 恵津子, 山之内 淳, 石井 寿幸, 久和 茂, 吉川 泰弘

    動脈硬化   ( 34回抄集 )   226 - 226   2002.6

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    Language：Japanese   Publisher：(一社)日本動脈硬化学会  

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  • 糖尿病APAハムスターのすい島における抗酸化物質(N-acetyl-L-cysteine)投与の効果

    高取敦志, 稲永敏明, 堀内恵子, 石井寿幸, 板垣慎一, 久和茂, 吉川泰弘

    日本獣医学会学術集会講演要旨集   134th   2002

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  • SZ誘発糖尿病APAハムスターにみられた大動脈解離の病理組織学的検索

    堀内恵子, 高取敦志, 稲永敏明, 太田恵津子, 山之内淳, 石井寿幸, 久和茂, 吉川泰弘

    日本動脈硬化学会総会プログラム・抄録集   34th   2002

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  • 慢性高血糖・高脂血症を呈するAPAハムスターすい島病変に対するプロブコール投与の影響

    高取敦志, 稲永敏明, 堀内恵子, 石井寿幸, 久和茂, 板垣慎一, 吉川泰弘

    日本獣医学会学術集会講演要旨集   132nd   2001

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  • 糖尿病APAハムスターにみられた大動脈解離

    堀内恵子, 山之内淳, 西田恵津子, 高取敦志, 稲永敏明, 石井和寿, 久和茂, 吉川泰弘

    日本獣医学会学術集会講演要旨集   132nd   2001

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Research Projects

  • Study of splicing factor ZRSR1 in spermatogenesis for therapeutic application

    Grant number：20K06448  2020.4 - 2023.3

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

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    Grant amount：\3900000 （ Direct Cost: \3000000 、 Indirect Cost：\900000 ）

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  • Functional analysis of WTAP protein complex on alternative splicing

    Grant number：26830124  2014.4 - 2016.3

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

    Horiuchi Keiko

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    Grant amount：\3900000 （ Direct Cost: \3000000 、 Indirect Cost：\900000 ）

    Wilms’ tumor 1-associating protein (WTAP) is a putative splicing regulator which is required for mouse early embryo development and cell cycle progression. We previously isolated the proteins which interact with WTAP, including VIRILIZER, CBLL1, KIAA0853, RBM15, BCLAF1, THRAP3 and general splicing regulators.To identify the alternative RNA splicing regulated by WTAP protein complex, we performed high-throughput mRNA sequencing using WTAP knockdown cells. Interestingly, WTAP regulates alternative splicing of histone H4 Lys 20 methyltransferases SUV420H1 and SUV420H2 by promoting a production of the truncated isoforms, leading to a change in the global H4K20 methylation level.

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  • Dynamics of Molecular Pattern Recognition in Protein Interaction

    Grant number：25220205  2013.5 - 2018.3

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

    HAMAKUBO TAKAO, Fujitani Hideaki, Nagatoishi Satoru, Yamashita Takefumi

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    Grant amount：\210600000 （ Direct Cost: \162000000 、 Indirect Cost：\48600000 ）

    In this study, we have analyzed the interaction pattern between PTX3 and histone, and obtained candidate molecules for regulating histone cytotoxicity in sepsis. Also we have detected direct interacting protein of WTAP and revealed the relation to alternative splicing of several target genes. We have obtained a candidate molecule which inhibits the interaction of WTAP and associating proteins. This should be a drug candidate as a RNA processing regulator in various biological phenomena. We identified a candidate peptide of aggregation prone part of PTX3 and interaction part in histone H3. Also we found the micro-particle release from histone damaged endothelial cells and developed specific antibodies to detect the identified marker proteins on the particle.

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  • Dynamic Proteomics of Transcriptional and Nuclear Architecture

    Grant number：20221010  2008 - 2012

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

    HAMAKUBO Takao, NAITO Makoto, MIYOSHI Motosuke, IHARA Shigeo, MOCHIZUKI Yasuhiro, IWANARI Hiroko, KAWAMURA Takeshi, SAKIHAMA Toshiko, DAIGO Kenji, HORIUCHI Keiko, OHTA Yoshihiro, OHASHI Riuko

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    Grant amount：\197080000 （ Direct Cost: \151600000 、 Indirect Cost：\45480000 ）

    In this study, we developed a highly sensitive quantitative proteomics analysis technique by using magnetic beads with immobilized specific antibodies. By generating highly specific monoclonal antibodies against HNF4-alpha, LXR-alpha, or WTAP, we have identified protein complexes for the transcriptional control of glucose metabolism related genes or RNA-processing machinery for the cell cycle control through distribution to nuclear speckles or nucleoli.

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  • The Dynamics of a novel protein complex involved in RNA processing and cell cycle regulation

    Grant number：20770134  2008 - 2009

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

    HORIUCHI Keiko

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    Grant amount：\3250000 （ Direct Cost: \2500000 、 Indirect Cost：\750000 ）

    Wilms' tumor 1-associating protein (WTAP) has been reported to be a ubiquitously expressed nuclear protein and supposed to have a role in pre-mRNA splicing. We have reported that WTAP is involved in the stability of cyclin A2 mRNA thereby regulates the cell cycle and WTAP knockout mice exhibited proliferative failure with death at early embryonic stage. In this study, we have developed a method for the functional analysis of protein-protein interactions for the endogenous proteins, by affinity purification mass spectrometry using magnetic beads and high-affinity antibodies. Using the method, we identified several binding proteins of WTAP, including vrilizer homolog, E3 ubiquitin ligase, SR proteins and RNA bindin proteins. Furthermore we found the compositional changes of WTAP protein complex in cell cycle, indicating a relation to cell cle regulation of WTAP protein complex.

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