Faculty Profiles - SUZUKI Hiroshi

Papers - SUZUKI Hiroshi

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Fibroblast growth factor signals regulate transforming growth factor-β-induced endothelial-to-myofibroblast transition of tumor endothelial cells via Elk1. Reviewed International journal

Akatsu Y, Takahashi N, Yoshimatsu Y, Kimuro S, Muramatsu T, Katsura A, Maishi N, Suzuki HI, Inazawa J, Hida K, Miyazono K, Watabe T

Molecular Oncology Vol. 13 ( 8 ) page： 1706 - 1724 2019.8

Gain-of-function mutation of microRNA-140 in human skeletal dysplasia. Reviewed International journal

Grigelioniene G, Suzuki HI, Taylan F, Mirzamohammadi F, Borochowitz ZU, Ayturk UM, Tzur S, Horemuzova E, Lindstrand A, Weis MA, Grigelionis G, Hammarsj? A, Marsk E, Nordgren A, Nordenskj?ld M, Eyre DR, Warman ML, Nishimura G, Sharp PA, Kobayashi T

Nature Medicine Vol. 25 ( 4 ) page： 583 - 590 2019.4

Lung fibroblasts express a miR-19a-19b-20a sub-cluster to suppress TGF-β-associated fibroblast activation in murine pulmonary fibrosis. Reviewed International journal

Kunihiko Souma, Shigeyuki Shichino, Shinichi Hashimoto, Satoshi Ueha, Tatsuya Tsukui, Takuya Nakajima, Hiroshi I Suzuki, Francis H W Shand, Yutaka Inagaki, Takahide Nagase, Kouji Matsushima

Scientific Reports Vol. 8 ( 1 ) page： 16642 - 16642 2018.11

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

Lung fibroblasts play a pivotal role in pulmonary fibrosis, a devastating lung disease, by producing extracellular matrix. MicroRNAs (miRNAs) suppress numerous genes post-transcriptionally; however, the roles of miRNAs in activated fibroblasts in fibrotic lungs remain poorly understood. To elucidate these roles, we performed global miRNA-expression profiling of fibroblasts from bleomycin- and silica-induced fibrotic lungs and investigated the functions of miRNAs in activated lung fibroblasts. Clustering analysis of global miRNA-expression data identified miRNA signatures exhibiting increased expression during fibrosis progression. Among these signatures, we found that a miR-19a-19b-20a sub-cluster suppressed TGF-β-induced activation of fibroblasts in vitro. Moreover, to elucidate whether fibroblast-specific intervention against the sub-cluster modulates pathogenic activation of fibroblasts in fibrotic lungs, we intratracheally transferred the sub-cluster-overexpressing fibroblasts into bleomycin-treated lungs. Global transcriptome analysis of the intratracheally transferred fibroblasts revealed that the sub-cluster not only downregulated expression of TGF-β-associated pro-fibrotic genes, including Acta2, Col1a1, Ctgf, and Serpine1, but also upregulated expression of the anti-fibrotic genes Dcn, Igfbp5, and Mmp3 in activated lung fibroblasts. Collectively, these findings indicated that upregulation of the miR-19a-19b-20a sub-cluster expression in lung fibroblasts counteracted TGF-β-associated pathogenic activation of fibroblasts in murine pulmonary fibrosis.

DOI： 10.1038/s41598-018-34839-0

PubMed

Evolution of weak cooperative interactions for biological specificity. Reviewed International journal

Gao A, Shrinivas K, Lepeudry P, Suzuki HI, Sharp PA, Chakraborty AK

Proc Natl Acad Sci U S A. Vol. 115 ( 47 ) page： E11053 - E11060 2018.11

An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1-Positive Lung Adenocarcinomas. Reviewed International journal

Naoya Miyashita, Masafumi Horie, Hiroshi I Suzuki, Masahito Yoshihara, Dijana Djureinovic, Johan Persson, Hans Brunnström, Cecilia Lindskog, Hedvig Elfving, Patrick Micke, Akira Saito, Takahide Nagase

Journal of Thoracic Oncology Vol. 13 ( 11 ) page： 1676 - 1691 2018.11

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

INTRODUCTION: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute family bHLH transcription factor 1 (ASCL1), common to high-grade neuroendocrine tumors, small-cell lung cancer and large cell neuroendocrine carcinoma. METHODS: The aim of this study was to characterize clinical and molecular features of ASCL1-positive lung adenocarcinoma by using recent transcriptome profiling in multiple patient cohorts and genome-wide epigenetic profiling including data from The Cancer Genome Atlas. RESULTS: The ASCL1-positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor EGFR mutations. In transcriptome profiling, this subtype overlapped with the recently proposed proximal-proliferative molecular subtype. Gene expression profiling of ASCL1-positive cases suggested generally poor immune cell infiltration and none of the tumors were positive for programmed cell death ligand 1 protein expression. Genome-wide methylation analysis showed global DNA hypomethylation in ASCL1-positive cases. ASCL1 was associated with super-enhancers in ASCL1-positive lung adenocarcinoma cells, and ASCL1 silencing suppressed other super-enhancer-associated genes, suggesting that ASCL1 acts as a master transcriptional regulator. This was further reinforced by the essential roles of ASCL1 in cell proliferation, survival, and cell cycle control. CONCLUSIONS: These results suggest that ASCL1 defines a subgroup of lung adenocarcinoma with distinct molecular features by driving super-enhancer-mediated transcriptional programs.

DOI： 10.1016/j.jtho.2018.07.096

PubMed

Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling. Reviewed International journal

Suzuki HI, Horie M, Mihira H, Saito A

J Vis Exp. ( 138 ) 2018.8

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

Phenotypic plasticity of endothelial cells underlies cardiovascular system development, cardiovascular diseases, and various conditions associated with organ fibrosis. In these conditions, differentiated endothelial cells acquire mesenchymal-like phenotypes. This process is called endothelial-mesenchymal transition (EndMT) and is characterized by downregulation of endothelial markers, upregulation of mesenchymal markers, and morphological changes. EndMT is induced by several signaling pathways, including transforming growth factor (TGF)-β, Wnt, and Notch, and regulated by molecular mechanisms similar to those of epithelial-mesenchymal transition (EMT) important for gastrulation, tissue fibrosis, and cancer metastasis. Understanding the mechanisms of EndMT is important to develop diagnostic and therapeutic approaches targeting EndMT. Robust induction of EndMT in vitro is useful to characterize common gene expression signatures, identify druggable molecular mechanisms, and screen for modulators of EndMT. Here, we describe an in vitro method for induction of EndMT. MS-1 mouse pancreatic microvascular endothelial cells undergo EndMT after prolonged exposure to TGF-β and show upregulation of mesenchymal markers and morphological changes as well as induction of multiple inflammatory chemokines and cytokines. Methods for the analysis of microRNA (miRNA) modulation are also included. These methods provide a platform to investigate mechanisms underlying EndMT and the contribution of miRNAs to EndMT.

DOI： 10.3791/57577

PubMed

MicroRNA Control of TGF-β Signaling. Reviewed International journal

Suzuki HI

International Journal of Molecular Sciences Vol. 19 ( 7 ) 2018.6

Deconvolution of seed and RNA-binding protein crosstalk in RNAi-based functional genomics. Reviewed International journal

Suzuki HI, Spengler RM, Grigelioniene G, Kobayashi T, Sharp PA

Nature Genetics Vol. 50 ( 5 ) page： 657 - 661 2018.5

Transcriptional Pause Sites Delineate Stable Nucleosome-Associated Premature Polyadenylation Suppressed by U1 snRNP. Reviewed International journal

Chiu AC, Suzuki HI, Wu X, Mahat DB, Kriz AJ, Sharp PA

Molecular Cell Vol. 69 ( 4 ) page： 648 - 663.e7 2018.2

HIF-1α promotes autophagic proteolysis of Dicer and enhances tumor metastasis. Reviewed International journal

Lai HH, Li JN, Wang MY, Huang HY, Croce CM, Sun HL, Lyu YJ, Kang JW, Chiu CF, Hung MC, Suzuki HI, Chen PS

Journal of Clinical Investigation Vol. 128 ( 2 ) page： 625 - 643 2018.2

TBX4 is involved in the super-enhancer-driven transcriptional programs underlying features specific to lung fibroblasts. Reviewed International journal

Masafumi Horie, Naoya Miyashita, Yu Mikami, Satoshi Noguchi, Yasuhiro Yamauchi, Maho Suzukawa, Takeshi Fukami, Ken Ohta, Yoshihide Asano, Shinichi Sato, Yoko Yamaguchi, Mitsuhiro Ohshima, Hiroshi I Suzuki, Akira Saito, Takahide Nagase

American journal of physiology. Lung cellular and molecular physiology Vol. 314 ( 1 ) page： L177-L191 - L191 2018.1

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

Lung fibroblasts participate in the pathogenesis of respiratory diseases, including lung cancer and pulmonary fibrosis. Although fibroblasts are ubiquitous constituents of various organs, their cellular diversity among different organs has been poorly characterized. Here, we aimed to investigate the distinct gene signature of lung fibroblasts that represents its pulmonary origin and the underlying gene regulatory networks. Promoter-level differential expression analysis by cap analysis of gene expression (CAGE) sequencing revealed distinct gene expression patterns of fibroblasts derived from different anatomical sites and identified 88 coding genes with higher expression in lung fibroblasts relative to other fibroblasts. Multiple key transcription factors important for lung mesenchyme development, including the T-box transcription factors TBX2, TBX4, and TBX5 were enriched in this lung-specific signature and were associated with super-enhancers. TBX4 showed highly specific expression in lung fibroblasts and was required for cell proliferation and collagen gel contraction capacity. Transcriptome analysis revealed that TBX4 could broadly regulate fibroblast-related pathways and partly contribute to super-enhancer-mediated transcriptional programs. Of pathological importance, lung fibroblast-specific genes were globally downregulated in lung cancer-associated fibroblasts (CAFs). Notably, TBX2, TBX4, and TBX5 were downregulated and hypermethylated in lung CAFs, suggesting an association between epigenetic silencing of these factors and phenotypic alteration of lung fibroblasts in cancer. Our study highlights the importance of T-box transcription factors, especially TBX4, and super-enhancers in the roles of lung fibroblasts in pulmonary physiology and pathogenesis.

DOI： 10.1152/ajplung.00193.2017

PubMed

Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy Reviewed International journal

Lior Nissim, Ming-Ru Wu, Erez Pery, Adina Binder-Nissim, Hiroshi I. Suzuki, Doron Stupp, Claudia Wehrspaun, Yuval Tabach, Phillip A. Sharp, Timothy K. Lu

Cell Vol. 171 ( 5 ) page： 1138 - + 2017.11

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

Despite its success in several clinical trials, cancer immunotherapy remains limited by the rarity of targetable tumor-specific antigens, tumor-mediated immune suppression, and toxicity triggered by systemic delivery of potent immunomodulators. Here, we present a proof-of-concept immunomodulatory gene circuit platform that enables tumor-specific expression of immunostimulators, which could potentially overcome these limitations. Our design comprised de novo synthetic cancer-specific promoters and, to enhance specificity, an RNA-based AND gate that generates combinatorial immunomodulatory outputs only when both promoters are mutually active. These outputs included an immunogenic cell-surface protein, a cytokine, a chemokine, and a checkpoint inhibitor antibody. The circuits triggered selective T cell-mediated killing of cancer cells, but not of normal cells, in vitro. In in vivo efficacy assays, lentiviral circuit delivery mediated significant tumor reduction and prolonged mouse survival. Our design could be adapted to drive additional immunomodulators, sense other cancers, and potentially treat other diseases that require precise immunological programming.

DOI： 10.1016/j.cell.2017.09.049

Web of Science

PubMed

Regulation of TGF-beta-mediated endothelial-mesenchymal transition by microRNA-27 Reviewed International journal

Hiroshi I. Suzuki, Akihiro Katsura, Hajime Mihira, Masafumi Horie, Akira Saito, Kohei Miyazono

Journal of Biochemistry Vol. 161 ( 5 ) page： 417 - 420 2017.5

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

Multiple microRNAs (miRNAs) regulate epithelial-mesenchymal transition and endothelial-mesenchymal transition (EndMT). Here we report that microRNA-27b (miR-27b) positively regulates transforming growth factor-beta (TGF-beta)-induced EndMT of MS-1 mouse pancreatic microvascular endothelial cells. TGF-beta induced miR-23b/24-1/27b expression, and inhibition of miR-27 suppressed TGF-beta-mediated induction of mesenchymal genes. Genome-wide miRNA target analysis revealed that miR-27 targets Elk1, which acts as a competitive inhibitor of myocardin-related transcription factor-serum response factor signalling and as a myogenic repressor. miR-27b was also found to regulate several semaphorin receptors including Neuropilin 2, Plexin A2 and Plexin D1. These results suggest important roles of miR-27 in TGF-beta-driven EndMT.

DOI： 10.1093/jb/mvx017

Web of Science

PubMed

Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis Reviewed International journal

Hiroshi I. Suzuki, Richard A. Young, Phillip A. Sharp

Cell Vol. 168 ( 6 ) page： 1000 - + 2017.3

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

Super-enhancers are an emerging subclass of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here, we report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA ( pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNAexpression and function. CRISPR/Cas9 genomics revealed that super-enhancer constituents act cooperatively and facilitate Drosha/DGCR8 recruitment and pri-miRNA processing to boost cell-specific miRNA production. The BET-bromodomain inhibitor JQ1 preferentially inhibits super-enhancerdirected cotranscriptional pri-miRNA processing. Furthermore, super-enhancers are characterized by pervasive interaction with DGCR8/Drosha and DGCR8/Drosha-regulated mRNA stability control, suggesting unique RNA regulation at super-enhancers. Finally, super-enhancers mark multiple miRNAsassociated with cancer hallmarks. This study presents principles underlying miRNA biology in health and disease and an unrecognized higher-order property of super-enhancers in RNA processing beyond transcription.

DOI： 10.1016/j.cell.2017.02.015

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PubMed

YAP and TAZ modulate cell phenotype in a subset of small cell lung cancer Reviewed International journal

Masafumi Horie, Akira Saito, Mitsuhiro Ohshima, Hiroshi I. Suzuki, Takahide Nagase

Cancer Science Vol. 107 ( 12 ) page： 1755 - 1766 2016.12

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Small cell lung cancer (SCLC) is a highly aggressive and metastatic malignancy that shows rapid development of chemoresistance and a high rate of recurrence. Recent genome and transcriptome studies have provided the whole landscape of genomic alterations and gene expression changes in SCLC. In light of the inter-individual heterogeneity of SCLC, subtyping of SCLC might be helpful for prediction of therapeutic response and prognosis. Based on the transcriptome data of SCLC cell lines, we undertook transcriptional network-defined SCLC classification and identified a unique SCLC subgroup characterized by relatively high expression of Hippo pathway regulators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) (YAP/TAZ subgroup). The YAP/TAZ subgroup displayed adherent cell morphology, lower expression of achaete-scute complex homolog 1 (ASCL1) and neuroendocrine markers, and higher expression of laminin and integrin. YAP knockdown caused cell morphological alteration reminiscent of floating growth pattern in many SCLC cell lines, and microarray analyses revealed a subset of genes regulated by YAP, including Ajuba LIM protein (AJUBA). AJUBA also contributed to cell morphology regulation. Of clinical importance, SCLC cell lines of the YAP/TAZ subgroup showed unique patterns of drug sensitivity. Our findings shed light on a subtype of SCLC with YAP and TAZ expression, and delineate molecular networks underlying the heterogeneity of SCLC.

DOI： 10.1111/cas.13078

Web of Science

PubMed

MicroRNA-31 is a positive modulator of endothelial-mesenchymal transition and associated secretory phenotype induced by TGF-beta Reviewed International journal

Akihiro Katsura, Hiroshi I. Suzuki, Toshihide Ueno, Hajime Mihira, Tomoko Yamazaki, Takahiko Yasuda, Tetsuro Watabe, Hiroyuki Mano, Yoshitsugu Yamada, Kohei Miyazono

Genes to Cells Vol. 21 ( 1 ) page： 99 - 116 2016.1

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Transforming growth factor- (TGF-) plays central roles in endothelial-mesenchymal transition (EndMT) involved in development and pathogenesis. Although EndMT and epithelial-mesenchymal transition are similar processes, roles of microRNAs in EndMT are largely unknown. Here, we report that constitutively active microRNA-31 (miR-31) is a positive regulator of TGF--induced EndMT. Although the expression is not induced by TGF-, miR-31 is required for induction of mesenchymal genes including -SMA, actin reorganization and MRTF-A activation during EndMT. We identified VAV3, a regulator of actin remodeling and MRTF-A activity, as a miR-31 target. Global transcriptome analysis further showed that miR-31 positively regulates EndMT-associated unique secretory phenotype (EndMT-SP) characterized by induction of multiple inflammatory chemokines and cytokines including CCL17, CX3CL1, CXCL16, IL-6 and Angptl2. As a mechanism for this phenomenon, TGF- and miR-31 suppress Stk40, a negative regulator of NF-B pathway. Interestingly, TGF- induces alternative polyadenylation (APA)-coupled miR-31-dependent Stk40 suppression without concomitant miR-31 induction, and APA-mediated exclusion of internal poly(A) sequence in Stk40 3UTR enhances target efficiency of Stk40. Finally, miR-31 functions as a molecular hub to integrate TGF- and TNF- signaling to enhance EndMT. These data confirm that constitutively active microRNAs, as well as inducible microRNAs, serve as phenotypic modifiers interconnected with transcriptome dynamics during EndMT.

DOI： 10.1111/gtc.12323

Web of Science

PubMed

Reduced Supply of Monocyte-Derived Macrophages Leads to a Transition from Nodular to Diffuse Lesions and Tissue Cell Activation in Silica-Induced Pulmonary Fibrosis in Mice Reviewed International journal

Shigeyuki Shichino, Jun Abe, Satoshi Ueha, Mikiya Otsuji, Tatsuya Tsukui, Mizuha Kosugi-Kanaya, Francis H. W. Shand, Shin-ichi Hashimoto, Hiroshi I. Suzuki, Teppei Morikawa, Yutaka Inagaki, Kouji Matsushima

American Journal of Pathology Vol. 185 ( 11 ) page： 2923 - 2938 2015.11

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Pulmonary fibrosis (PF) is an intractable disorder with a poor prognosis. Lung macrophages have been reported to regulate both progression and remission of bleomycin-induced diffuse PP. However, it remains unclear how macrophages contribute to silica-induced progressive nodular PF and the associated tissue cell responses in vivo. We found that lack of monocyte-derived macrophages results in the formation of diffuse PP after silica instillation. We found that the proportion and the number of monocyte-derived macrophages were persistently higher in silica-induced progressive PF compared with bleomycin-induced PP. Surprisingly, in Ccr2(-/-) mice, in which monocyte-derived macrophage infiltration is impaired, silica administration induced diffuse PF with loose nodule formation and greater activation of tissue cells. In the diffuse lesions, the distribution of epithelial cells, distribution of myofibroblasts, and architecture of the basement membrane were disrupted. Consistent with the development of diffuse Lesions, genes that were differentially expressed in CD45(-) tissue cells from the lung of wild-type and Ccr2(-/-) mice were highly enriched in human diffuse, progressive PF. In gene ontology network analyses, many of these genes were associated with tissue remodeling and included genes not previously associated with PF, such as Mmp14, Thbs2, and Fgfr4. Overall, these results indicate that monocyte-derived macrophages prevent transition from nodular to diffuse silica-induced PF, potentially by regulating tissue cell responses.

DOI： 10.1016/j.ajpath.2015.07.013

Web of Science

PubMed

A clinically attainable dose of L-asparaginase targets glutamine addiction in lymphoid cell lines Reviewed International journal

Koichi Sugimoto, Hiroshi I. Suzuki, Tsutomu Fujimura, Asami Ono, Naoko Kaga, Yasushi Isobe, Makoto Sasaki, Hikari Taka, Kohei Miyazono, Norio Komatsu

Cancer Science Vol. 106 ( 11 ) page： 1534 - 1543 2015.11

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

L-asparaginase (L-ASNase) is an important branch of chemotherapy for acute lymphoblastic leukemia (ALL) and some types of non-Hodgkin's lymphoma, including natural killer (NK)-cell lymphoma. Although it mediates hydrolysis of asparagine (Asn) and glutamine (Gln), which are variably required for cancer cell survival, the relative contribution of Asn and Gln depletion to the anti-tumor activity in therapeutic doses is unclear in ALL and malignant lymphoma. Here we demonstrate that L-ASNase exerts cytotoxicity through targeting the Gln addiction phenotype in lymphoid cell lines. A clinically attainable intermediate dose of L-ASNase induced massive apoptosis in ALL Jurkat and mantle cell lymphoma Jeko cell lines, while a low dose of L-ASNase effectively killed NK-cell lymphoma cells. In the lymphoid cell lines Jurkat and Jeco, deprivation of Gln but not Asn specifically suppressed cell growth and survival, and phenocopied the action of L-ASNase. L-ASNase treatment and Gln deprivation dramatically disrupted the refilling of the tricarboxylic acid (TCA) cycle by intracellular glutamate (Glu) and disturbed the mitochondrial integrity, which were alleviated by various anaplerotic TCA cycle intermediates, suggesting a direct contribution of glutaminase activity of L-ASNase. The action of L-ASNase differs between Jurkat cells and NK-cell lymphoma cells, according to their dependence on Gln and Asn. Furthermore, we observed that high expression of glutaminase GLS1 is associated with increased sensivity to L-ASNase in pediatric B lineage ALL. Our results redefine L-ASNase as a therapeutic agent targeting Gln addiction in certain lymphoid cells and offer an additional basis for predicting L-ASNase sensitivity and engineering selective L-ASNase derivatives for leukemia and lymphoma.

DOI： 10.1111/cas.12807

Web of Science

PubMed

A role of uridylation pathway for blockade of let-7 microRNA biogenesis by Lin28B Reviewed International journal

Hiroshi I. Suzuki, Akihiro Katsura, Kohei Miyazono

Cancer Science Vol. 106 ( 9 ) page： 1174 - 1181 2015.9

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

The precise control of microRNA (miRNA) biosynthesis is crucial for gene regulation. Lin28A and Lin28B are selective inhibitors of biogenesis of let-7 miRNAs involved in development and tumorigenesis. Lin28A selectively inhibits let-7 biogenesis through cytoplasmic uridylation of precursor let-7 by TUT4 terminal uridyl transferase and subsequent degradation by Dis3l2 exonuclease. However, a role of this uridylation pathway remains unclear in let-7 blockade by Lin28B, a paralog of Lin28A, while Lin28B is reported to engage a distinct mechanism in the nucleus to suppress let-7. Here we revisit a functional link between Lin28B and the uridylation pathway with a focus on let-7 metabolism in cancer cells. Both Lin28A and Lin28B interacted with Dis3l2 in the cytoplasm, and silencing of Dis3l2 upregulated uridylated pre-let-7 in both Lin28A- and Lin28B-expressing cancer cell lines. In addition, we found that amounts of let-7 precursors influenced intracellular localization of Lin28B. Furthermore, we found that MCPIP1 (Zc3h12a) ribonuclease was also involved in degradation of both non-uridylated and uridylated pre-let-7. Cancer transcriptome analysis showed association of expression levels of Lin28B and uridylation pathway components, TUT4 and Dis3l2, in various human cancer cells and hepatocellular carcinoma. Collectively, these results suggest that cytoplasmic uridylation pathway actively participates in blockade of let-7 biogenesis by Lin28B.

DOI： 10.1111/cas.12721

Web of Science

PubMed

Small-RNA asymmetry is directly driven by mammalian Argonautes Reviewed International journal

Hiroshi I. Suzuki, Akihiro Katsura, Takahiko Yasuda, Toshihide Ueno, Hiroyuki Mano, Koichi Sugimoto, Kohei Miyazono

Nature Structural & Molecular Biology Vol. 22 ( 7 ) page： 512 - + 2015.7

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

Asymmetric selection of single-stranded guide RNAs from double-stranded RNA precursors is crucial in RNA silencing-mediated gene regulation. However, the precise mechanisms of small-RNA asymmetry are unclear, especially because asymmetric selection can still occur when the putative asymmetry sensors Drosophila R2D2 and mammalian Dicer are depleted. Here we report a direct contribution of mammalian Argonaute 2 (Ago2) to microRNA (miRNA) asymmetry. Ago2 selects strands with 5'-uridine or 5'-adenosine and thermodynamically unstable 5' ends in parallel through its two sensor regions, which contact the 5' nucleobases and 5'-phosphates of prospective guide strands. Hence, miRNA asymmetry shows superposed patterns reflecting 5'-end nucleotide identity ('digital' pattern) and thermodynamic stability ('analog' pattern). Furthermore, we demonstrate that cancer-associated miRNA variations reprogram asymmetric selection. Finally, our study presents a model of this universal principle, to aid in comprehensive understanding of miRNA function and development of new RNA-silencing therapies in precision medicine.

DOI： 10.1038/nsmb.3050

Web of Science

PubMed

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Papers - SUZUKI Hiroshi