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Morphometric Analysis of the Eye by Magnetic Resonance Imaging in MGST2-Gene-Deficient Mice 招待査読

Chaomulige, Toshihiko Matsuo, Kohei Sugimoto, Mary Miyaji, Osamu Hosoya, Masashi Ueda, Ryosuke Kobayashi, Takuro Horii, Izuho Hatada

Biomedicines 12 ( 2 ) 370 - 370 2024年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Strabismus, a neuro-ophthalmological condition characterized by misalignment of the eyes, is a common ophthalmic disorder affecting both children and adults. In our previous study, we identified the microsomal glutathione S-transferase 2 (MGST2) gene as one of the potential candidates for comitant strabismus susceptibility in a Japanese population. The MGST2 gene belongs to the membrane-associated protein involved in the generation of pro-inflammatory mediators, and it is also found in the protection against oxidative stress by decreasing the reactivity of oxidized lipids. To look for the roles of the MGST2 gene in the development, eye alignment, and overall morphology of the eye as the possible background of strabismus, MGST2 gene knockout (KO) mice were generated by CRISPR/Cas9-mediated gene editing with guide RNAs targeting the MGST2 exon 2. The ocular morphology of the KO mice was analyzed through high-resolution images obtained by a magnetic resonance imaging (MRI) machine for small animals. The morphometric analyses showed that the height, width, and volume of the eyeballs in MGST2 KO homozygous mice were significantly greater than those of wild-type mice, indicating that the eyes of MGST2 KO homozygous mice were significantly enlarged. There were no significant differences in the axis length and axis angle. These morphological changes may potentially contribute to the development of a subgroup of strabismus.

DOI： 10.3390/biomedicines12020370

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Selective DNA-binding of SP120 (rat ortholog of human hnRNP U) is mediated by arginine-glycine rich domain and modulated by RNA 査読

18 ( 8 ) e0289599 - e0289599 2023年8月

ATM suppresses c-Myc overexpression in the mammary epithelium in response to estrogen 査読

Rifat Ara Najnin, Md Rasel Al Mahmud, Md Maminur Rahman, Shunichi Takeda, Hiroyuki Sasanuma, Hisashi Tanaka, Yasuhiro Murakawa, Naoto Shimizu, Salma Akter, Masatoshi Takagi, Takuro Sunada, Shusuke Akamatsu, Gang He, Junji Itou, Masakazu Toi, Mary Miyaji, Kimiko M. Tsutsui, Scott Keeney, Shintaro Yamada

Cell Reports 42 ( 1 ) 111909 - 111909 2023年1月

Candidate Genes in Testing Strategies for Linkage Analysis and Bioinformatic Sorting of Whole Genome Sequencing Data in Three Small Japanese Families with Idiopathic Superior Oblique Muscle Palsy 査読

Toshihiko Matsuo, Chaomulige, Mary Miyaji, Osamu Hosoya, Akira Saito, Kazuyuki Nakazono

International Journal of Molecular Sciences 23 ( 15 ) 8626 - 8626 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Idiopathic superior oblique muscle palsy is a major type of paralytic, non-comitant strabismus and presents vertical and cyclo-torsional deviation of one eye against the other eye, with a large vertical fusion range and abnormal head posture such as head tilt. Genetic background is considered to play a role in its development, as patients with idiopathic superior oblique muscle palsy have varying degrees of muscle hypoplasia and, rarely, the complete absence of the muscle, that is, aplasia. In this study, whole genome sequencing was performed, and single nucleotide variations and short insertions/deletions (SNVs/InDels) were annotated in two patients each in three small families (six patients in total) with idiopathic superior oblique muscle palsy, in addition to three normal individuals in one family. At first, linkage analysis was carried out in the three families and SNVs/InDels in chromosomal loci with negative LOD scores were excluded. Next, SNVs/InDels shared by the six patients, but not by the three normal individuals, were chosen. SNVs/InDels were further narrowed down by choosing low-frequency (<1%) or non-registered SNVs/InDels in four databases for the Japanese population, and then by choosing SNVs/InDels with functional influence, leading to one candidate gene, SSTR5-AS1 in chromosome 16. The six patients were heterozygous for 13-nucleotide deletion in SSTR5-AS1, except for one homozygous patient, while the three normal individuals were wild type. Targeted polymerase chain reaction (PCR) and direct sequencing of PCR products confirmed the 13-nucleotide deletion in SSTR5-AS1. In the face of newly-registered SSTR5-AS1 13-nucleotide deletion at a higher frequency in a latest released database for the Japanese population, the skipping of low-frequency and non-registration sorting still resulted in only 13 candidate genes including SSTR5-AS1 as common variants. The skipping of linkage analysis also led to the same set of 13 candidate genes. Different testing strategies that consisted of linkage analysis and simple unintentional bioinformatics could reach candidate genes in three small families with idiopathic superior oblique muscle palsy.

DOI： 10.3390/ijms23158626

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Effect of NK-5962 on Gene Expression Profiling of Retina in a Rat Model of Retinitis Pigmentosa 招待査読

Shihui Liu, Mary Miyaji, Osamu Hosoya, Toshihiko Matsuo

International Journal of Molecular Sciences 22 ( 24 ) 13276 - 13276 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Purpose: NK-5962 is a key component of photoelectric dye-coupled polyethylene film, designated Okayama University type-retinal prosthesis (OUReP™). Previously, we found that NK-5962 solution could reduce the number of apoptotic photoreceptors in the eyes of the Royal College of Surgeons (RCS) rats by intravitreal injection under a 12 h light/dark cycle. This study aimed to explore possible molecular mechanisms underlying the anti-apoptotic effect of NK-5962 in the retina of RCS rats. Methods: RCS rats received intravitreal injections of NK-5962 solution in the left eye at the age of 3 and 4 weeks, before the age of 5 weeks when the speed in the apoptotic degeneration of photoreceptors reaches its peak. The vehicle-treated right eyes served as controls. All rats were housed under a 12 h light/dark cycle, and the retinas were dissected out at the age of 5 weeks for RNA sequence (RNA-seq) analysis. For the functional annotation of differentially expressed genes (DEGs), the Metascape and DAVID databases were used. Results: In total, 55 up-regulated DEGs, and one down-regulated gene (LYVE1) were found to be common among samples treated with NK-5962. These DEGs were analyzed using Gene Ontology (GO) term enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway analyses. We focused on the up-regulated DEGs that were enriched in extracellular matrix organization, extracellular exosome, and PI3K–Akt signaling pathways. These terms and pathways may relate to mechanisms to protect photoreceptor cells. Moreover, our analyses suggest that SERPINF1, which encodes pigment epithelium-derived factor (PEDF), is one of the key regulatory genes involved in the anti-apoptotic effect of NK-5962 in RCS rat retinas. Conclusions: Our findings suggest that photoelectric dye NK-5962 may delay apoptotic death of photoreceptor cells in RCS rats by up-regulating genes related to extracellular matrix organization, extracellular exosome, and PI3K–Akt signaling pathways. Overall, our RNA-seq and bioinformatics analyses provide insights in the transcriptome responses in the dystrophic RCS rat retinas that were induced by NK-5962 intravitreal injection and offer potential target genes for developing new therapeutic strategies for patients with retinitis pigmentosa.

DOI： 10.3390/ijms222413276

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A modified Tet-ON system minimizing leaky expression for cell-type specific gene induction in medaka fish. 査読

Osamu Hosoya, Myung Chung, Satoshi Ansai, Hideaki Takeuchi, Mary Miyaji

Development, growth & differentiation 2021年8月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

The Tet-ON system is an important molecular tool for temporally and spatially-controlled inducible gene expression. Here, we developed a Tet-ON system to induce transgene expression specifically in the rod photoreceptors of medaka fish. Our modified reverse tetracycline-controlled transcriptional transactivator (rtTAm) with 5 amino acid substitutions dramatically improved the leakiness of the transgene in medaka fish. We generated a transgenic line carrying a self-reporting vector with the rtTAm gene driven by the Xenopus rhodopsin promoter and a tetracycline response element (TRE) followed by the green fluorescent protein (GFP) gene. We demonstrated that GFP fluorescence was restricted to the rod photoreceptors in the presence of doxycycline in larval fish (9 days post-fertilization). The GFP fluorescence intensity was enhanced with longer durations of doxycycline treatment up to 72 h and in a dose-dependent manner (5-45 μg/ml). These findings demonstrate that the Tet-ON system using rtTAm allows for spatiotemporal control of transgene expression, at least in the rod photoreceptors, in medaka fish.

DOI： 10.1111/dgd.12743

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The Effect of Cyanine Dye NK-4 on Photoreceptor Degeneration in a Rat Model of Early-Stage Retinitis Pigmentosa. 査読国際誌

Shihui Liu, Toshihiko Matsuo, Mary Miyaji, Osamu Hosoya

Pharmaceuticals (Basel, Switzerland) 14 ( 7 ) 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

The present study aimed to evaluate the effects of NK-4 on the apoptosis of photoreceptors in a rat model of retinitis pigmentosa and explore the mechanism underlying anti-apoptosis activity. The Royal College of Surgeons (RCS) rats received an intravitreous injection of NK-4 solution in the left eye and vehicle control in the right eye. Apoptosis was detected by TUNEL method in frozen sections of the eyes. The retinal tissues of the rats were dissected for RNA-seq analysis. Functional and pathway enrichment analyses of differentially expressed genes (DEGs) were performed by using Metascape and DAVID software. The expression levels of DEGs were confirmed by real-time quantitative PCR (RT-qPCR). The number of apoptotic cells decreased in the outer nuclear layer (ONL) and the thickness of the ONL was significantly thicker in the retina of NK-4-injected eyes, compared with control eyes. Five DEGs were identified by RNA-seq analysis, and Hmox1, Mt1, Atf5, Slc7a11, and Bdh2 were confirmed to be up-regulated by RT-qPCR. Functional and pathway enrichment analysis of the up-regulated genes showed that anti-apoptosis effects of NK-4 in the retina of RCS rats may be related to the pathways of metal ion homeostasis, negative regulation of neuron death, response to toxic substance, and pigment metabolic process. We found a potential mechanism of NK-4, providing a new viewpoint for the development of more therapeutic uses of NK-4 in the future.

DOI： 10.3390/ph14070694

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Topoisomerase IIβ targets DNA crossovers formed between distant homologous sites to induce chromatin opening 査読国際誌

Mary Miyaji, Ryohei Furuta, Osamu Hosoya, Kuniaki Sano, Norikazu Hara, Ryozo Kuwano, Jiyoung Kang, Masaru Tateno, Kimiko M. Tsutsui, Ken Tsutsui

Scientific Reports 10 ( 1 ) 18550 - 18550 2020年12月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

<title>Abstract</title>
Type II DNA topoisomerases (topo II) flip the spatial positions of two DNA duplexes, called G- and T- segments, by a cleavage-passage-resealing mechanism. In living cells, these DNA segments can be derived from distant sites on the same chromosome. Due to lack of proper methodology, however, no direct evidence has been described so far. The beta isoform of topo II (topo IIβ) is essential for transcriptional regulation of genes expressed in the final stage of neuronal differentiation. Here we devise a genome-wide mapping technique (eTIP-seq) for topo IIβ target sites that can measure the genomic distance between G- and T-segments. It revealed that the enzyme operates in two distinctive modes, termed proximal strand passage (PSP) and distal strand passage (DSP). PSP sites are concentrated around transcription start sites, whereas DSP sites are heavily clustered in small number of hotspots. While PSP represent the conventional topo II targets that remove local torsional stresses, DSP sites have not been described previously. Most remarkably, DSP is driven by the pairing between homologous sequences or repeats located in a large distance. A model-building approach suggested that topo IIβ acts on crossovers to unknot the intertwined DSP sites, leading to chromatin decondensation.

DOI： 10.1038/s41598-020-75004-w

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その他リンク： http://www.nature.com/articles/s41598-020-75004-w

Topoisomerase IIβ targets DNA crossovers formed between distant homologous sites to modulate chromatin structure and gene expression

Mary Miyaji, Ryohei Furuta, Osamu Hosoya, Kuniaki Sano, Norikazu Hara, Ryozo Kuwano, Jiyoung Kang, Masaru Tateno, Kimiko M. Tsutsui, Ken Tsutsui

BioRXiV 2018年12月

担当区分：筆頭著者出版者・発行元：Cold Spring Harbor Laboratory

<title>Abstract</title><sec><title>Background</title>Type II DNA topoisomerases (topo II) flip the spatial positions of two DNA duplexes, called G- and T-segments, by a cleavage-passage-resealing mechanism. In living cells, these DNA segments can be placed far from each other on the same chromosome. However, no direct evidence for this to occur has been described so far due to lack of proper methodology.

</sec><sec><title>Results</title>The beta isoform of topo II (topo IIβ) is essential for transcriptional regulation of genes expressed in the final stage of neuronal differentiation. To elucidate the enzyme’s role in the process, here we devise a genome-wide mapping technique for topo IIβ target sites that can measure the genomic distance between G- and T-segments. It became clear that the enzyme operates in two distinctive modes, termed proximal strand passage (PSP) and distal strand passage (DSP). PSP sites are concentrated around transcription start sites, whereas DSP sites are heavily clustered in small number of hotspots. While PSP represent the conventional topo II targets that remove local torsional stresses, DSP sites have not been described previously. Most remarkably, DSP is driven by the pairing between homologous sequences or repeats located in a large distance. A model-building approach suggested that the DSP sites are intertwined or knotted and topo IIβ is engaged in unknotting reaction that leads to chromatin decondensation and gene regulation.

</sec><sec><title>Conclusions</title>When combined with categorized gene expression analysis, the model-based prediction of DSP sites reveals that DSP is one of the key factors for topo IIβ-dependency of neuronal gene regulation.

</sec>

DOI： 10.1101/484956

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Genomic regions targeted by DNA topoisomerase IIβ frequently interact with a nuclear scaffold/matrix protein hnRNP U/SAF-A/SP120. 査読

Miyaji M, Furuta R, Sano K, Tsutsui KM, Tsutsui K

Journal of cellular biochemistry 116 ( 4 ) 677 - 685 2015年4月

Retinoic Acid-Induced Epidermal Transdifferentiation in Skin 査読

Journal of Developmental Biology 2 ( 3 ) 158 - 173 2014年6月

Nuclear dynamics of topoisomerase IIβ reflects its catalytic activity that is regulated by binding of RNA to the C-terminal domain. 査読

Onoda A, Hosoya O, Sano K, Kiyama K, Kimura H, Kawano S, Furuta R, Miyaji M, Tsutsui K, Tsutsui KM

Nucleic acids research 42 ( 14 ) 9005 - 9020 2014年

Tgm2/Gh, Gbx1 and TGF-beta are involved in retinoic acid-induced transdifferentiation from epidermis to mucosal epithelium 査読

The International Jarnal of Develomental Biology 55 ( 10 ) 933 - 943 2011年

Regulation of DNA topoisomerase IIbeta through RNA-dependent association with heterogeneous nuclear ribonucleoprotein U (hnRNP U). 査読

Kawano, S, Miyaji, M, Ichiyasu, S, Tsutsui,K.M, Tsutsui, K

J. Biol. Chem., 285 ( 34 ) 26451 - 26460 2010年

[Regulation of neuronal gene expression by DNA topoisomerase IIbeta]. 査読

Tsutsui K, Tsutsui KM, Miyaji M, Sano K

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 54 ( 11 ) 1333 - 1343 2009年9月

Topoisomerase IIβ activates a subset of neuronal genes that are repressed in AT-rich genomic environment 査読

Sano K, Miyaji, Yamaguchi M, Tsutsui KM, Tsutsui K

PLoS ONE 3 ( 12 ) e4103 - 13 2008年12月

Histone acetylation-independent transcription stimulation by a histone chaperone. 査読

Kato K, Miyaji-Yamaguchi M, Okuwaki M, Nagata K

Nucleic Acids Res. 35 ( 3 ) 705 - 707 2007年

Synergistic action of MLL, a TRX protein with template activating factor-I, a histone chaperone. 査読

Shimoyama T, Kato K, Miyaji-Yamaguchi M, Nagata K

FEBS Lett. 579 ( 3 ) 757 - 762 2005年

Aberrant intracellular localization of SET-CAN fusion protein, associated with a leukemia, disorganizes nuclear export. 査読

Saito S, Miyaji-Yamaguchi M, Nagata K

Int. J. Cancer. 111 ( 4 ) 501 - 507 2004年

Involvement of nucleocytoplasmic shuttling of yeast Nap1 in mitotic progression. 査読

Miyaji-Yamaguchi M, Kato K, Nakano R, Akashi T, Kikuchi A, Nagata K

Mol. Cell. Biol. 23 ( 18 ) 6672 - 6684 2003年

S1A03クロマチンシャペロンの分子機能

永田恭介, Gyurcsik Bela, 春木宏人, 宮地-山口まり, 奥脇暢, 高橋剛, 三原久和

生物物理 41 S1 2001年

Sperm chromatin decondensation by template activating factor I through direct interaction with basic proteins 査読

K Matsumoto, K Nagata, M Miyaji-Yamaguchi, A Kikuchi, M Tsujimoto

MOLECULAR AND CELLULAR BIOLOGY 19 ( 10 ) 6940 - 6952 1999年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC MICROBIOLOGY

Template activating factor I (TAF-I) was originally identified as a host factor required for DNA replication and transcription of adenovirus genome complexed with viral basic proteins. Purified TAF-I was shown to bind to core histones and stimulate transcription from nucleosomal templates. Human TAF-I consists of two acidic proteins, TAF-I alpha and TAF-I beta, which differ from each other only in their amino-terminal regions. Here, we report that TAF-I decondenses demembraned Xenopus sperm chromatin. Human TAF-I beta has a chromatin decondensation activity comparable to that of NAP-I, another histone binding protein, whereas TAF-I alpha has only a weak activity. Analysis of molecular mechanisms underlying the chromatin decondensation by TAF-I revealed that TAF-I interacts directly with sperm basic proteins. Deletion of the TAF-I carboxyl-terminal acidic region abolishes the decondensation activity. Interestingly, the acidic region itself is not sufficient for decondensation, since an amino acid substitution mutant in the dimerization domain of TAF-I which has the intact acidic region does not support chromatin decondensation. We detected the beta form of TAF-I in Xenopus oocytes and eggs by immunoblotting, and the cloning of its cDNA led us to conclude that Xenopus TAF-I beta also decondenses sperm chromatin. These results suggest that TAF-I plays a role in remodeling higher-order chromatin structure as well as nucleosomal structure through direct interaction with chromatin basic proteins.

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Coiled-coil structure-mediated dimerization of template activating factor-I is critical for its chromatin remodeling activity 査読

M Miyaji-Yamaguchi, M Okuwaki, K Nagata

JOURNAL OF MOLECULAR BIOLOGY 290 ( 2 ) 547 - 557 1999年7月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS LTD

Template activating factor-I (TAF-I)alpha and TAF-I beta have been identified as the host factors that activate DNA replication of the adenovirus genome complexed with viral basic core proteins (Ad core). TAF-I causes a structural change of the Ad core, thereby stimulating not only replication but also transcription from the Ad core DNA in vitro. TAF-I also activates transcription from the reconstituted chromatin consisting of DNA fragments and purified histones through chromatin remodeling. Although the carboxyl-terminal region, which is highly rich in acidic amino acids, is essential for the TAF-I activity, it remains unclear how other parts are involved in its activity. The native TAF-I isolated from HeLa cells exists as either hetero- or homo-oligomer. Here, we have demonstrated by cross-linking assays that most of TAF-I exists as a dimer. Analyses using deletion mutant TAF-I proteins revealed that the amino-terminal region of TAF-I common to both alpha and beta is essential for dimerization. This region is predicted to form a coiled-coil structure. Indeed, mutations disrupting this putative structure abolished the dimerization capability and reduced the TAF-I activity in the Ad core DNA replication assay. Furthermore, we found that TAF-I mutants lacking the acidic tail act in a dominant-negative manner in this assay. These observations strongly suggest that the dimerization of TAF-I is important for its activity. (C) 1999 Academic Press.

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Functional domains of template-activating factor-I as a protein phosphatase 2A inhibitor 査読

S Saito, M Miyaji-Yamaguchi, T Shimoyama, K Nagata

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 259 ( 2 ) 471 - 475 1999年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC

Template-Activating Factor-1 (TAF-1) alpha and beta, chromatin remodeling factors, were identified as the stimulatory factor for replication of the adenovirus DNA complexed with viral basic core proteins. Recently, two cellular inhibitors for protein phosphatase 2A (PP2A) have been isolated. One of these inhibitors, designated I-2(PP2A), is a truncated version of TAF-1 beta. Here, it is shown using recombinant TAF-1 proteins that both TAF-1 alpha and beta have the PP2A inhibitor activity. The N-terminal region but not the C-terminal acidic region, the latter of which is essential for the chromatin remodeling activity, is shown to be required for the PP2A inhibitor activity. Roles of TAF-1 alpha- and beta-specific regions, the C-terminal acidic region, and other regions of TAF-1 for the PP2A inhibitor activity are also discussed. (C) 1999 Academic Press.

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NAP-I is a functional homologue of TAF-I that is required for replication and transcription of the adenovirus genome in a chromatin-like structure 査読

H Kawase, M Okuwaki, M Miyaji, R Ohba, H Handa, Y Ishimi, T FujiiNakata, A Kikuchi, K Nagata

GENES TO CELLS 1 ( 12 ) 1045 - 1056 1996年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BLACKWELL SCIENCE LTD

Background: For the activation of replication and transcription from DNA in a chromatin structure, a variety of factors are thought to be needed that alter the chromatin structure. Template activating factor-I (TAF-I) has been identified as such a host factor required for replication of the adenovirus (Ad) genome complexed with viral basic core proteins (Ad core). TAF-I also stimulates transcription from the Ad core DNA.
Results: Using mutant TAF-I proteins, we have demonstrated that the acidic stretch present in the carboxyl terminal region is essential for the stimulation of transcription from the Ad core. A genomic footprinting experiment with restriction endonuclease has revealed that TAF-I causes a structural change in the Ad core. TAP-I has been shown to have significant amino acid similarity to nucleosome assembly protein-I (NAP-I), which is involved in the formation of the chromatin structure. We have shown that TAF-I can be substituted by NAP-I in the activation of the cell-free Ad core transcription system. Two of the tripartite acidic regions and the region homologous to TAF-I in NAP-I are required for the maximal TAF-I activity of NAP-I. Furthermore, TAF-I has been shown to have NAP-I activity, and the acidic region of TAP-I is required for this activity.
Conclusions: Since TAF-I causes the structural change of the Ad core and thereby activates transcription, TAF-I is thought to be one of the proteins which is involved in chromatin remodeling. NAP-I is structurally related to TAF-I and functionally substitutes for TAF-I. Furthermore, TAF-I has NAP-I activity. These observations suggest that this type of molecule has dual functions, possibly by participating in facilitating the assembly of the chromatin structure as well as perturbing the chromatin structure to allow transcription to proceed.

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