研究者詳細 - 黒柳　秀人

論文 - 黒柳　秀人

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UNC5B is an isoform-dependent target for ectodomain shedding.

Kotaro Sugimoto, Eichi Watabe, Mio Takuma, Kaname Nagahara, Toshinori Sawano, Mihoko Kajita, Junichi Takagi, Hidehito Kuroyanagi, Kyoko Shirakabe

The Journal of Biochemistry ( Oxford University Press ) mvaf043 2025年07月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Cytoplasmic mutant RBM20 causes arrhythmogenicity in murine atria.

Kensuke Ihara, Satoshi Iwamiya, Masaki Ikuta, Yurie Soejima, Yuichi Hiraoka, Atsushi Nakano, Susumu Minamisawa, Tetsushi Furukawa, Hidehito Kuroyanagi, Tetsuo Sasano

Journal of Molecular and Cellular Cardiology ( Elsevier Ltd. ) 205 ( August 2025 ) 1 - 12 2025年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Profiling of RBM20-Regulated CaMKIIδ Splice Variants Across the Heart, Skeletal Muscle, and Olfactory Bulbs.

Yui Maeda, Yuri Yamasu, Hidehito Kuroyanagi

Genes to Cells ( John Wiley & Sons, Inc. ) 30 ( 3 ) e70021 2025年05月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

関連する研究費コード: JP20K21385, JP23K18221, JP22H04925

Calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ), encoded by the Camk2d gene, plays key regulatory roles in various Ca2+-regulated cellular processes. Extensive alternative splicing of the Camk2d gene generates multiple CaMKIIδ splice variants that exhibit differential roles. Despite significant advances in understanding the functions of CaMKIIδ, the full repertoire of Camk2d splice variants in a variety of tissues and their distinct roles in physiological and pathological contexts remain incompletely characterized due to the complex nature of multiple alternative splicing events. Here, we conducted long-read amplicon sequencing to investigate the murine Camk2d splice variants in the heart, skeletal muscle, and olfactory bulbs and show that Camk2d mRNAs in the heart and skeletal muscle have shorter 3'UTRs. Our results in this study suggest that a key regulator of Camk2d splicing, RNA-binding motif protein 20 (RBM20), whose gain-of-function mutations cause dilated cardiomyopathy, is crucial for the expression of heart-specific splice variants. Olfactory bulbs specifically express novel splice variants that utilize a mutually exclusive exon 6B and/or an alternative polyadenylation site in a novel exon 17.5 in an RBM20-inependent manner. The tissue-specific repertoire of CaMKIIδ splice variants and their aberrant expression in disease model animals will help in understanding their roles in physiological and pathological contexts.

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Alternative splicing of a single exon causes a major impact on the affinity of Caenorhabditis elegans tropomyosin isoforms for actin filaments.

Shoichiro Ono, Eichi Watabe, Keita Morisaki, Kanako Ono, Hidehito Kuroyanagi

Frontiers in Cell and Developmental Biology ( Frontiers Media S.A. ) 11 1208913 2023年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

関連する研究費コード: JP20H04839, JP20H03181

Tropomyosin is generally known as an actin-binding protein that regulates actomyosin interaction and actin filament stability. In metazoans, multiple tropomyosin isoforms are expressed, and some of them are involved in generating subpopulations of actin cytoskeleton in an isoform-specific manner. However, functions of many tropomyosin isoforms remain unknown. Here, we report identification of a novel alternative exon in the #ICaenorhabditis elegans#IR tropomyosin gene and characterization of the effects of alternative splicing on the properties of tropomyosin isoforms. Previous studies have reported six tropomyosin isoforms encoded by the #IC. elegans lev-11#IR tropomyosin gene. We identified a seventh isoform, LEV-11U, that contained a novel alternative exon, exon 7c (E7c). LEV-11U is a low-molecular-weight tropomyosin isoform that differs from LEV-11T only at the exon 7-encoded region. #IIn silico#IR analyses indicated that the E7c-encoded peptide sequence was unfavorable for coiled-coil formation and distinct from other tropomyosin isoforms in the pattern of electrostatic surface potentials. #IIn vitro#IR, LEV-11U bound poorly to actin filaments, whereas LEV-11T bound to actin filaments in a saturable manner. When these isoforms were transgenically expressed in the #IC. elegans#IR striated muscle, LEV-11U was present in the diffuse cytoplasm with tendency to form aggregates, whereas LEV-11T co-localized with sarcomeric actin filaments. Worms with a mutation in E7c showed reduced motility and brood size, suggesting that this exon is important for the optimal health. These results indicate that alternative splicing of a single exon can produce biochemically diverged tropomyosin isoforms and suggest that a tropomyosin isoform with poor actin affinity has a novel biological function.

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Simultaneous measurement of nascent transcriptome and translatome using 4-thiouridine metabolic RNA labeling and translating ribosome affinity purification.

Hirotatsu Imai, Daisuke Utsumi, Hidetsugu Torihara, Kenzo Takahashi, Hidehito Kuroyanagi, Akio Yamashita

Nucleic Acids Research ( Oxford University Press ) 51 ( 14 ) e76 2023年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

関連する研究費コード: JP20H04839, JP20H03181

Regulation of gene expression in response to various biological processes, including extracellular stimulation and environmental adaptation requires nascent RNA synthesis and translation. Analysis of the coordinated regulation of dynamic RNA synthesis and translation is required to determine functional protein production. However, reliable methods for the simultaneous measurement of nascent RNA synthesis and translation at the gene level are limited. Here, we developed a novel method for the simultaneous assessment of nascent RNA synthesis and translation by combining 4-thiouridine (4sU) metabolic RNA labeling and translating ribosome affinity purification (TRAP) using a monoclonal antibody against evolutionarily conserved ribosomal P-stalk proteins. The P-stalk-mediated TRAP (P-TRAP) technique recovered endogenous translating ribosomes, allowing easy translatome analysis of various eukaryotes. We validated this method in mammalian cells by demonstrating that acute unfolded protein response (UPR) in the endoplasmic reticulum (ER) induces dynamic reprogramming of nascent RNA synthesis and translation. Our nascent P-TRAP (nP-TRAP) method may serve as a simple and powerful tool for analyzing the coordinated regulation of transcription and translation of individual genes in various eukaryotes.

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Structure of the Caenorhabditis elegans m6A methyltransferase METT10 that regulates SAM homeostasis.

Jue Ju, Tomohiko Aoyama, Yuka Yashiro, Seisuke Yamashita, Hidehito Kuroyanagi, Kozo Tomita

Nucleic Acids Research ( Oxford University Press ) 51 ( 5 ) 2434 - 2446 2023年02月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

関連する研究費コード: JP20H03181, JP17H05596, JP20H04839

In #ICaenorhabditis elegans#IR, the N#U6#UR-methyladenosine (m#U6#URA) modification by METT10, at the 3'-splice sites in #IS#IR-adenosyl-L-methionine (SAM) synthetase (#Isams#IR) precursor mRNA (pre-mRNA), inhibits #Isams#IR pre-mRNA splicing, promotes alternative splicing coupled with nonsense-mediated decay of the pre-mRNAs, and thereby maintains the cellular SAM level. Here, we present structural and functional analyses of #IC. elegans#IR METT10. The structure of the N-terminal methyltransferase domain of METT10 is homologous to that of human METTL16, which installs the m#U6#URA modification in the 3'-UTR hairpins of methionine adenosyltransferase (#IMAT2A#IR) pre-mRNA and regulates the MAT2A pre-mRNA splicing/stability and SAM homeostasis. Our biochemical analysis suggested that #IC. elegans#IR METT10 recognizes the specific structural features of RNA surrounding the 3'-splice sites of #Isams#IR pre-mRNAs, and shares a similar substrate RNA recognition mechanism with human METTL16. #IC. elegans#IR METT10 also possesses a previously unrecognized functional C-terminal RNA-binding domain, kinase associated 1 (KA-1), which corresponds to the vertebrate-conserved region (VCR) of human METTL16. As in human METTL16, the KA-1 domain of #IC. elegans#IR METT10 facilitates the m#U6#URA modification of the 3'-splice sites of #Isams#IR pre-mRNAs. These results suggest the well-conserved mechanisms for the m#U6#URA modification of substrate RNAs between #IHomo sapiens#IR and #IC. elegans#IR, despite their different regulation mechanisms for SAM homeostasis.

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ナンセンスコドン介在的mRNA分解（NMD）と共役した選択的スプライシングによる遺伝子発現の制御

黒柳秀人

生化学 ( 公益社団法人日本生化学会 ) 94 ( 6 ) 868 - 874 2022年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

筆者らは，線虫のナンセンスコドン介在的mRNA分解（NMD）欠損変異株を利用して，全長mRNAの直接シーケンシング解析により，NMDの基質となるスプライスバリアントの網羅的探索を行い，259遺伝子の289バリアントを同定した．このうち，S-アデノシル-L-メチオニン（SAM）合成酵素をコードするsams遺伝子群では，SAMの濃度に応じて3′スプライス部位のAGジヌクレオチドのアデニン塩基がN6-メチルアデノシン（m6A）修飾を受けることで発現量が間接的にフィードバック制御されるという新奇の制御機構の発見に至った．本稿では，直接RNAシーケンシング解析を利用したmRNA全長配列解析やsams遺伝子の発現量の選択的スプライシングによる制御の意義などについて概説する．

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I536T variant of RBM20 affects splicing of cardiac structural proteins that are causative for developing dilated cardiomyopathy.

Takuma Yamamoto, Rie Sano, Aya Miura, Mai Imasaka, Yoshiro Naito, Minori Nishiguchi, Kensuke Ihara, Naruhito Otani, Yoshihiko Kominato, Masaki Ohmuraya, Hidehito Kuroyanagi & Hajime Nishio

Journal of Molecular Medicine ( Springer Nature ) 100 ( 12 ) 1741 - 1754 2022年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

関連する研究費コード: JP20K07659, JP20K21385

RBM20 is one of the genes predisposing to dilated cardiomyopathy (DCM). Variants in the RS domain have been reported in many DCM patients, but the pathogenicity of variants within the RNA-recognition motif remains unknown. Two human patients with the I536T-RBM20 variant without an apparent DCM phenotype were identified in sudden death cohorts. A splicing reporter assay was performed, and an I538T knock-in mouse model (Rbm20I538T) was generated to determine the significance of this variant. The reporter assay demonstrated that the human I536T variant affected the TTN splicing pattern compared to wild-type. In the mouse experiments, Rbm20I538T mice showed different splicing patterns in Ttn, Ldb3, Camk2d, and Ryr2. The expressions of Casq1, Mybpc2, and Myot were upregulated in Rbm20I538T mice, but Rbm20I538T mice showed neither DCM nor cardiac dysfunction on histopathological examination and ultrasound echocardiography. The I536T-RBM20 (I538T-Rbm20) variant changes gene splicing and affects gene expression, but the splicing and expression changes in Ttn and Ca handling genes such as Casq1, Camk2d, and Ryr2 do not cause DCM morphology in the mouse model.

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Periostin Exon-21 Antibody Neutralization of Triple-Negative Breast Cancer Cell-Derived Periostin Regulates Tumor-Associated Macrophage Polarization and Angiogenesis.

Tatsuya Fujikawa, Fumihiro Sanada, Yoshiaki Taniyama, Kana Shibata, Naruto Katsuragi, Nobutaka Koibuchi, Kaori Akazawa, Yuko Kanemoto, Hidehito Kuroyanagi, Kenzo Shimazu, Hiromi Rakugi and Ryuichi Morishita

Cancers ( MDPI ) 13 ( 20 ) 5072 - 5072 2021年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

関連する研究費コード: JP20K07659, JP20H03181 and JP20K21385

Periostin (Pn) is involved in multiple processes of cancer progression. Previously, we reported that Pn expression is correlated with mesenchymal tumor markers and poor prognosis in triple-negative breast cancer (TNBC). In the TNBC xenograft model, chemotherapy increased expression of a Pn alternative splicing variant (ASV) with exon 21, and administration of the neutralizing antibody against Pn with exon 21 (Pn-21 Ab) overcame chemoresistance with a reduction in the mesenchymal cancer cell fraction. In the present study, the role of Pn ASV with exon 21 in TNBC progression has been addressed. We first established a stable cell line carrying a fluorescence-based splicing reporter. Pn-positive TNBC has higher expression of genes related to tumor-associated macrophage (TAM) recruitment and ECM-receptor interaction than Pn-negative cells. In a xenograft model, only Pn-positive cells initiated tumor formation, and the Pn-21 Ab suppressed tumor cell growth, accompanied by decreased M2 TAM polarization and the number of tumor vessels. These data suggest that cancer cell-derived Pn ASV educates TAMs and regulates angiogenesis, which in turn establishes a microenvironmental niche that is supportive of TNBC.

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Loss of Caenorhabditis elegans homologue of human MOB4 compromises life span, health life span and thermotolerance.

Momotaj Jahan, Hiroaki Iwasa, Hidehito Kuroyanagi, Yutaka Hata

Genes to Cells ( The Molecular Biology Society of Japan/John Wiley & Sons Australia, Ltd ) 26 ( 10 ) 798 - 806 2021年08月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Mob1/phocein family proteins are conserved from yeast to mammals. Human has four MOB genes, MOB1, 2, 3 and 4. Human MOB1 protein, which is a component of the Hippo pathway, is involved in the inhibition of yes-associated protein (YAP1) through large tumor suppressor (LATS) kinases and plays a tumor suppressive role. In contrast, MOB4 activates YAP1. Caernorhabditis elegans (C. elegans) also has four MOB genes. Moreover, C. elegans has homologues of YAP1 (Ce_YAP-1) and LATS kinases (WTS-1). Nevertheless, our previous study revealed that the Hippo pathway is not conserved in C. elegans and that heat shock activates Ce_YAP-1. We also reported that Ce_YAP-1 is involved in the regulation of life span, healthy lifespan and thermotolerance. In this study, we raised a question whether and how C. elegans homologue of MOB4 (Ce_MOB-4) is involved in the regulation of Ce_YAP-1. Ce_MOB-4 is ubiquitously expressed in adult worms. This expression pattern is similar to that of Ce_YAP-1. mob-4 loss-of-function mutants show short life span, short health life span and compromise thermotolerance. However, heat shock activates Ce_YAP-1 in mob-4 mutant. In conclusion, the role of MOB4 in the activation of YAP1 is not conserved in C. elegans.

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m6A-mediated alternative splicing coupled with nonsense-mediated mRNA decay regulates SAM synthetase homeostasis.

Eichi Watabe, Marina Togo-Ohno, Yuma Ishigami, Shotaro Wani, Keiko Hirota, Mariko Kimura-Asami, Sharmin Hasan, Satomi Takei, Akiyoshi Fukamizu, Yutaka Suzuki, Tsutomu Suzuki, Hidehito Kuroyanagi

The EMBO Journal ( EMBO Press ) 40 ( 14 ) e106434 2021年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

関連する研究費コード: JP20H03181, JP18H05272, JP20H04839, JP17K07746, JP17H01519, JP23116004, JP16H06279, JP26113003, JP20112004, JP24657116, JP25118506, JP15H01467, JP26291003, JP15H01350, JP15KK0252, JP17H05596, JP17H03633, 1D102, JPMJER2002

Alternative splicing of pre-mRNAs can regulate gene expression levels by coupling with nonsense-mediated mRNA decay (NMD). In order to elucidate a repertoire of mRNAs regulated by alternative splicing coupled with NMD (AS-NMD) in an organism, we performed long-read RNA sequencing of poly(A)+ RNAs from an NMD-deficient mutant strain of Caenorhabditis elegans, and obtained full-length sequences for mRNA isoforms from 259 high-confidence AS-NMD genes. Among them are the S-adenosyl-L-methionine (SAM) synthetase (sams) genes sams-3 and sams-4. SAM synthetase activity autoregulates sams gene expression through AS-NMD in a negative feedback loop. We furthermore find that METT-10, the orthologue of human U6 snRNA methyltransferase METTL16, is required for the splicing regulation in vivo, and specifically methylates the invariant AG dinucleotide at the distal 3' splice site (3'SS) in vitro. Direct RNA sequencing coupled with machine learning confirms m6A modification of endogenous sams mRNAs. Overall, these results indicate that homeostasis of SAM synthetase in C. elegans is maintained by alternative splicing regulation through m6A modification at the 3'SS of the sams genes.

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Author Correction: Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs

Jay W. Schneider, Saji Oommen, Muhammad Y. Qureshi, Sean C. Goetsch, David R. Pease, Rhianna S. Sundsbak, Wei Guo, Mingming Sun, Han Sun, Hidehito Kuroyanagi, Dennis A. Webster, Alexander W. Coutts, Kimberly A. Holst, Brooks S. Edwards, Nikolas Newville, Matthew A. Hathcock, Tamene Melkamu, Francesca Briganti, Wu Wei, Maria G. Romanelli, Scott C. Fahrenkrug, Doug E. Frantz, Timothy M. Olson, Lars M. Steinmetz, Daniel F. Carlson, Timothy J. Nelson & Wanek Program Preclinical Pipeline

Nature Medicine ( Springer Nature Limited ) 27 ( 7 ) 1309 2021年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs.

Nature Medicine ( Springer Nature Limited ) 26 ( 11 ) 1788 - 1800 2020年11月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Ribonucleoprotein (RNP) granules are biomolecular condensates-liquid-liquid phase-separated droplets that organize and manage messenger RNA metabolism, cell signaling, biopolymer assembly, biochemical reactions and stress granule responses to cellular adversity. Dysregulated RNP granules drive neuromuscular degenerative disease but have not previously been linked to heart failure. By exploring the molecular basis of congenital dilated cardiomyopathy (DCM) in genome-edited pigs homozygous for an RBM20 allele encoding the pathogenic R636S variant of human RNA-binding motif protein-20 (RBM20), we discovered that RNP granules accumulated abnormally in the sarcoplasm, and we confirmed this finding in myocardium and reprogrammed cardiomyocytes from patients with DCM carrying the R636S allele. Dysregulated sarcoplasmic RBM20 RNP granules displayed liquid-like material properties, docked at precisely spaced intervals along cytoskeletal elements, promoted phase partitioning of cardiac biomolecules and fused with stress granules. Our results link dysregulated RNP granules to myocardial cellular pathobiology and heart failure in gene-edited pigs and patients with DCM caused by RBM20 mutation.

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A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fibrillation in mice.

Kensuke Ihara, Tetsuo Sasano, Yuichi Hiraoka, Marina Togo-Ohno, Yurie Soejima, Motoji Sawabe, Megumi Tsuchiya, Hidesato Ogawa, Tetsushi Furukawa & Hidehito Kuroyanagi

Scientific Reports ( Springer Nature ) 10 ( 1 ) 17894 - 17894 2020年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

関連する研究費コード: JP20K21385

Dilated cardiomyopathy (DCM) is a fatal heart disease characterized by left ventricular dilatation and cardiac dysfunction. Recent genetic studies on DCM have identified causative mutations in over 60 genes, including RBM20, which encodes a regulator of heart-specific splicing. DCM patients with RBM20 mutations have been reported to present with more severe cardiac phenotypes, including impaired cardiac function, atrial fibrillation (AF), and ventricular arrhythmias leading to sudden cardiac death, compared to those with mutations in the other genes. An RSRSP stretch of RBM20, a hotspot of missense mutations found in patients with idiopathic DCM, functions as a crucial part of its nuclear localization signals. However, the relationship between mutations in the RSRSP stretch and cardiac phenotypes has never been assessed in an animal model. Here, we show that Rbm20 mutant mice harboring a missense mutation S637A in the RSRSP stretch, mimicking that in a DCM patient, demonstrated severe cardiac dysfunction and spontaneous AF and ventricular arrhythmias mimicking the clinical state in patients. In contrast, Rbm20 mutant mice with frame-shifting deletion demonstrated less severe phenotypes, although loss of RBM20-dependent alternative splicing was indistinguishable. RBM20S637A protein cannot be localized to the nuclear speckles, but accumulated in cytoplasmic, perinuclear granule-like structures in cardiomyocytes, which might contribute to the more severe cardiac phenotypes.

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mRNA Editing, Processing and Quality Control in Caenorhabditis elegans

Joshua A Arribere, Hidehito Kuroyanagi, Heather A Hundley

Genetics ( Genetics Society of America ) 215 ( 3 ) 531 - 568 2020年07月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

関連する研究費コード: JP20112004, JP25118506, JP26291003, JP15H01350, JP15H01467, JP15KK0252, JP17H03633, JP17H05596, JP20H03181, JP221S0002 and JP16H06279 (PAGS)

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Alternative splicing of the Caenorhabditis elegans lev-11 tropomyosin gene is regulated in a tissue-specific manner.

Watabe E, Ono S, Kuroyanagi H

Cytoskeleton (Hoboken, N.J.) 75 ( 10 ) 427 - 436 2018年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Tropomyosin isoforms contribute to generation of functionally divergent actin filaments. In the nematode Caenorhabditis elegans, multiple isoforms are produced from lev‐11, the single tropomyosin gene, by combination of two separate promoters and alternative pre‐mRNA splicing. In this study, we report that alternative splicing of lev‐11 is regulated in a tissue‐specific manner so that a particular tropomyosin isoform is expressed in each tissue. Reverse‐transcription polymerase chain reaction analysis of lev‐11 mRNAs confirms five previously reported isoforms (LEV‐11A, LEV‐11C, LEV‐11D, LEV‐11E and LEV‐11O) and identifies a new sixth isoform LEV‐11T. Using transgenic alternative‐splicing reporter minigenes, we find distinct patterns of preferential exon selections in the pharynx, body wall muscles, intestine and neurons. The body wall muscles preferentially process splicing to produce high‐molecular‐weight isoforms, LEV‐11A, LEV‐11D and LEV‐11O. The pharynx specifically processes splicing to express a low‐molecular‐weight isoform LEV‐11E, whereas the intestine and neurons process splicing to express another low‐molecular‐weight isoform LEV‐11C. The splicing pattern of LEV‐11T was not predominant in any of these tissues, suggesting that this is a minor isoform. Our results suggest that regulation of alternative splicing is an important mechanism to express proper tropomyosin isoforms in particular tissue and/or cell types in C. elegans.

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UNC119 is a binding partner of tumor suppressor Ras-association domain family 6 and induces apoptosis and cell cycle arrest by MDM2 and p53.

Iwasa H, Sarkar A, Shimizu T, Sawada T, Hossain S, Xu X, Maruyama J, Arimoto-Matsuzaki K, Withanage K, Nakagawa K, Kurihara H, Kuroyanagi H, Hata Y

Cancer science 109 ( 9 ) 2767 - 2780 2018年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Ras-association domain family 6 (RASSF6) is a tumor suppressor that interacts with MDM2 and stabilizes p53. Caenorhabditis elegans unc-119 encodes a protein that is required for normal development of the nervous system. Humans have 2 unc-119 homologues, UNC119 and UNC119B. We have identified UNC119 as a RASSF6-interacting protein. UNC119 promotes the interaction between RASSF6 and MDM2 and stabilizes p53. Thus, UNC119 induces apoptosis by RASSF6 and p53. UNC119 depletion impairs DNA repair after DNA damage and results in polyploid cell generation. These findings support that UNC119 is a regulator of the RASSF6-MDM2-p53 axis and functions as a tumor suppressor.

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Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization.

Murayama R, Kimura-Asami M, Togo-Ohno M, Yamasaki-Kato Y, Naruse TK, Yamamoto T, Hayashi T, Ai T, Spoonamore KG, Kovacs RJ, Vatta M, Iizuka M, Saito M, Wani S, Hiraoka Y, Kimura A, Kuroyanagi H

Scientific reports ( Nature Publishing Group ) 8 ( 1 ) 8970 - 8970 2018年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

RBM20 is a major regulator of heart-specific alternative pre-mRNA splicing of TTN encoding a giant sarcomeric protein titin. Mutation in RBM20 is linked to autosomal-dominant familial dilated cardiomyopathy (DCM), yet most of the RBM20 missense mutations in familial and sporadic cases were mapped to an RSRSP stretch in an arginine/serine-rich region of which function remains unknown. In the present study, we identified an R634W missense mutation within the stretch and a G1031X nonsense mutation in cohorts of DCM patients. We demonstrate that the two serine residues in the RSRSP stretch are constitutively phosphorylated and mutations in the stretch disturb nuclear localization of RBM20. Rbm20 S637A knock-in mouse mimicking an S635A mutation reported in a familial case showed a remarkable effect on titin isoform expression like in a patient carrying the mutation. These results revealed the function of the RSRSP stretch as a critical part of a nuclear localization signal and offer the Rbm20 S637A mouse as a good model for in vivo study.

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Tropomyosin isoforms differentially affect muscle contractility in the head and body regions of the nematode Caenorhabditis elegans.

Barnes DE, Watabe E, Ono K, Kwak E, Kuroyanagi H, Ono S

Molecular biology of the cell ( American Society for Cell Biology ) 29 ( 9 ) 1075 - 1088 2018年05月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Tropomyosin, one of the major actin filament–binding proteins, regulates actin–myosin interaction and actin-filament stability. Multicellular organisms express a number of tropomyosin isoforms, but understanding of isoform-specific tropomyosin functions is incomplete. The nematode Caenorhabditis elegans has a single tropomyosin gene, lev-11, which has been reported to express four isoforms by using two separate promoters and alternative splicing. Here, we report a fifth tropomyosin isoform, LEV-11O, which is produced by alternative splicing that includes a newly identified seventh exon, exon 7a. By visualizing specific splicing events in vivo, we find that exon 7a is predominantly selected in a subset of the body wall muscles in the head, while exon 7b, which is the alternative to exon 7a, is utilized in the rest of the body. Point mutations in exon 7a and exon 7b cause resistance to levamisole-induced muscle contraction specifically in the head and the main body, respectively. Overex-pression of LEV-11O, but not LEV-11A, in the main body results in weak levamisole resistance. These results demonstrate that specific tropomyosin isoforms are expressed in the head and body regions of the muscles and contribute differentially to the regulation of muscle contractility.

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Alternative Splicing Regulator RBM20 and Cardiomyopathy.

Watanabe T, Kimura A, Kuroyanagi H

Frontiers in molecular biosciences 5 ( NOV ) 105 2018年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

RBM20 is a vertebrate-specific RNA-binding protein with two zinc finger (ZnF) domains, one RNA-recognition motif (RRM)-type RNA-binding domain and an arginine/serine (RS)-rich region. RBM20 has initially been identified as one of dilated cardiomyopathy (DCM)-linked genes. RBM20 is a regulator of heart-specific alternative splicing and Rbm20ΔRRM mice lacking the RRM domain are defective in the splicing regulation. The Rbm20ΔRRM mice, however, do not exhibit a characteristic DCM-like phenotype such as dilatation of left ventricles or systolic dysfunction. Considering that most of the RBM20 mutations identified in familial DCM cases were heterozygous missense mutations in an arginine-serine-arginine-serine-proline (RSRSP) stretch whose phosphorylation is crucial for nuclear localization of RBM20, characterization of a knock-in animal model is awaited. One of the major targets for RBM20 is the TTN gene, which is comprised of the largest number of exons in mammals. Alternative splicing of the TTN gene is exceptionally complicated and RBM20 represses >160 of its consecutive exons, yet detailed mechanisms for such extraordinary regulation are to be elucidated. The TTN gene encodes the largest known protein titin, a multi-functional sarcomeric structural protein specific to striated muscles. As titin is the most important factor for passive tension of cardiomyocytes, extensive heart-specific and developmentally regulated alternative splicing of the TTN pre-mRNA by RBM20 plays a critical role in passive stiffness and diastolic function of the heart. In disease models with diastolic dysfunctions, the phenotypes were rescued by increasing titin compliance through manipulation of the Ttn pre-mRNA splicing, raising RBM20 as a potential therapeutic target.

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