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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 呂勝春 | |
| dc.contributor.author | Chia-Ling Hsieh | en |
| dc.contributor.author | 謝佳玲 | zh_TW |
| dc.date.accessioned | 2021-06-07T18:18:56Z | - |
| dc.date.copyright | 2012-03-02 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-01-31 | |
| dc.identifier.citation | Alisi, A., Spaziani, A., Anticoli, S., Ghidinelli, M., and Balsano, C. (2008). PKR is a novel functional direct player that coordinates skeletal muscle differentiation via p38MAPK/AKT pathways. Cell Signal 20, 534-542.
Amor, D.J., Kalitsis, P., Sumer, H., and Choo, K.H. (2004). Building the centromere: from foundation proteins to 3D organization. Trends Cell Biol 14, 359-368. Apponi, L.H., Corbett, A.H., and Pavlath, G.K. (2011). RNA-binding proteins and gene regulation in myogenesis. Trends Pharmacol Sci 32, 652-658. Barbon, A., Vallini, I., La Via, L., Marchina, E., and Barlati, S. (2003). Glutamate receptor RNA editing: a molecular analysis of GluR2, GluR5 and GluR6 in human brain tissues and in NT2 cells following in vitro neural differentiation. Brain Res Mol Brain Res 117, 168-178. Bass, B.L. (2002). RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem 71, 817-846. Bass, B.L., Nishikura, K., Keller, W., Seeburg, P.H., Emeson, R.B., O'Connell, M.A., Samuel, C.E., and Herbert, A. (1997). A standardized nomenclature for adenosine deaminases that act on RNA. RNA 3, 947-949. Bermudez, V.P., Farina, A., Tappin, I., and Hurwitz, J. (2010). Influence of the human cohesion establishment factor Ctf4/AND-1 on DNA replication. J Biol Chem 285, 9493-9505. Birch, J.L., Tan, B.C., Panov, K.I., Panova, T.B., Andersen, J.S., Owen-Hughes, T.A., Russell, J., Lee, S.C., and Zomerdijk, J.C. (2009). FACT facilitates chromatin transcription by RNA polymerases I and III. The EMBO journal 28, 854-865. Burattini, S., Ferri, P., Battistelli, M., Curci, R., Luchetti, F., and Falcieri, E. (2004). C2C12 murine myoblasts as a model of skeletal muscle development: morpho-functional characterization. Eur J Histochem 48, 223-233. Cam, H.P., Sugiyama, T., Chen, E.S., Chen, X., FitzGerald, P.C., and Grewal, S.I. (2005). Comprehensive analysis of heterochromatin- and RNAi-mediated epigenetic control of the fission yeast genome. Nat Genet 37, 809-819. Ceruti, S., Giammarioli, A.M., Camurri, A., Falzano, L., Rufini, S., Frank, C., Fiorentini, C., Malorni, W., and Abbracchio, M.P. (2000). Adenosine- and 2-chloro-adenosine-induced cytopathic effects on myoblastic cells and myotubes: involvement of different intracellular mechanisms. Neuromuscul Disord 10, 436-446. Chen, E.S., Zhang, K., Nicolas, E., Cam, H.P., Zofall, M., and Grewal, S.I. (2008). Cell cycle control of centromeric repeat transcription and heterochromatin assembly. Nature 451, 734-737. Cheng, M., Nguyen, M.H., Fantuzzi, G., and Koh, T.J. (2008). Endogenous interferon-gamma is required for efficient skeletal muscle regeneration. Am J Physiol Cell Physiol 294, C1183-1191. Clerzius, G., Gelinas, J.F., Daher, A., Bonnet, M., Meurs, E.F., and Gatignol, A. (2009). ADAR1 interacts with PKR during human immunodeficiency virus infection of lymphocytes and contributes to viral replication. J Virol 83, 10119-10128. Cottle, D.L., McGrath, M.J., Cowling, B.S., Coghill, I.D., Brown, S., and Mitchell, C.A. (2007). FHL3 binds MyoD and negatively regulates myotube formation. J Cell Sci 120, 1423-1435. de la Serna, I.L., Roy, K., Carlson, K.A., and Imbalzano, A.N. (2001). MyoD can induce cell cycle arrest but not muscle differentiation in the presence of dominant negative SWI/SNF chromatin remodeling enzymes. J Biol Chem 276, 41486-41491. Errico, A., Cosentino, C., Rivera, T., Losada, A., Schwob, E., Hunt, T., and Costanzo, V. (2009). Tipin/Tim1/And1 protein complex promotes Pol alpha chromatin binding and sister chromatid cohesion. EMBO J 28, 3681-3692. Eymery, A., Callanan, M., and Vourc'h, C. (2009a). The secret message of heterochromatin: new insights into the mechanisms and function of centromeric and pericentric repeat sequence transcription. Int J Dev Biol 53, 259-268. Eymery, A., Horard, B., El Atifi-Borel, M., Fourel, G., Berger, F., Vitte, A.L., Van den Broeck, A., Brambilla, E., Fournier, A., Callanan, M., et al. (2009b). A transcriptomic analysis of human centromeric and pericentric sequences in normal and tumor cells. Nucleic Acids Res 37, 6340-6354. Fernandez, H.R., Kavi, H.H., Xie, W., and Birchler, J.A. (2005). Heterochromatin: on the ADAR radar? Curr Biol 15, R132-134. Formosa, T., and Nittis, T. (1999). Dna2 mutants reveal interactions with Dna polymerase alpha and Ctf4, a Pol alpha accessory factor, and show that full Dna2 helicase activity is not essential for growth. Genetics 151, 1459-1470. Frescas, D., Guardavaccaro, D., Kuchay, S.M., Kato, H., Poleshko, A., Basrur, V., Elenitoba-Johnson, K.S., Katz, R.A., and Pagano, M. (2008). KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state. Cell Cycle 7, 3539-3547. Fukagawa, T. (2004). Centromere DNA, proteins and kinetochore assembly in vertebrate cells. Chromosome Res 12, 557-567. George, C.X., Das, S., and Samuel, C.E. (2008). Organization of the mouse RNA-specific adenosine deaminase Adar1 gene 5'-region and demonstration of STAT1-independent, STAT2-dependent transcriptional activation by interferon. Virology 380, 338-343. George, C.X., Li, Z., Okonski, K.M., Toth, A.M., Wang, Y., and Samuel, C.E. (2009). Tipping the balance: antagonism of PKR kinase and ADAR1 deaminase functions by virus gene products. J Interferon Cytokine Res 29, 477-487. George, C.X., and Samuel, C.E. (1999a). Characterization of the 5'-flanking region of the human RNA-specific adenosine deaminase ADAR1 gene and identification of an interferon-inducible ADAR1 promoter. Gene 229, 203-213. George, C.X., and Samuel, C.E. (1999b). Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible. Proc Natl Acad Sci U S A 96, 4621-4626. George, C.X., Wagner, M.V., and Samuel, C.E. (2005). Expression of interferon-inducible RNA adenosine deaminase ADAR1 during pathogen infection and mouse embryo development involves tissue-selective promoter utilization and alternative splicing. J Biol Chem 280, 15020-15028. Gommans, W.M., and Maas, S. (2008). Characterization of ADAR1-mediated modulation of gene expression. Biochem Biophys Res Commun 377, 170-175. Hanna, J.S., Kroll, E.S., Lundblad, V., and Spencer, F.A. (2001). Saccharomyces cerevisiae CTF18 and CTF4 are required for sister chromatid cohesion. Molecular and cellular biology 21, 3144-3158. Hartner, J.C., Walkley, C.R., Lu, J., and Orkin, S.H. (2009). ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol 10, 109-115. Iizasa, H., and Nishikura, K. (2009). A new function for the RNA-editing enzyme ADAR1. Nat Immunol 10, 16-18. Jonstrup, A.T., Thomsen, T., Wang, Y., Knudsen, B.R., Koch, J., and Andersen, A.H. (2008). Hairpin structures formed by alpha satellite DNA of human centromeres are cleaved by human topoisomerase IIalpha. Nucleic Acids Res 36, 6165-6174. Kafatos, F.C., Jones, C.W., and Efstratiadis, A. (1979). Determination of nucleic acid sequence homologies and relative concentrations by a dot hybridization procedure. Nucleic Acids Res 7, 1541-1552. Kanellopoulou, C., Muljo, S.A., Kung, A.L., Ganesan, S., Drapkin, R., Jenuwein, T., Livingston, D.M., and Rajewsky, K. (2005). Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev 19, 489-501. Kawakubo, K., and Samuel, C.E. (2000). Human RNA-specific adenosine deaminase (ADAR1) gene specifies transcripts that initiate from a constitutively active alternative promoter. Gene 258, 165-172. Kohler, A., Schmidt-Zachmann, M.S., and Franke, W.W. (1997). AND-1, a natural chimeric DNA-binding protein, combines an HMG-box with regulatory WD-repeats. J Cell Sci 110 ( Pt 9), 1051-1062. Koutsoulidou, A., Mastroyiannopoulos, N.P., Furling, D., Uney, J.B., and Phylactou, L.A. Expression of miR-1, miR-133a, miR-133b and miR-206 increases during development of human skeletal muscle. BMC Dev Biol 11, 34. Kronfeld-Kinar, Y., Vilchik, S., Hyman, T., Leibkowicz, F., and Salzberg, S. (1999). Involvement of PKR in the regulation of myogenesis. Cell Growth Differ 10, 201-212. Lai, F., Drakas, R., and Nishikura, K. (1995). Mutagenic analysis of double-stranded RNA adenosine deaminase, a candidate enzyme for RNA editing of glutamate-gated ion channel transcripts. J Biol Chem 270, 17098-17105. Lehmann, K.A., and Bass, B.L. (1999). The importance of internal loops within RNA substrates of ADAR1. J Mol Biol 291, 1-13. Lehnertz, B., Ueda, Y., Derijck, A.A., Braunschweig, U., Perez-Burgos, L., Kubicek, S., Chen, T., Li, E., Jenuwein, T., and Peters, A.H. (2003). Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr Biol 13, 1192-1200. Lei, H., Oh, S.P., Okano, M., Juttermann, R., Goss, K.A., Jaenisch, R., and Li, E. (1996). De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development 122, 3195-3205. Liu, H., Tan, B.C., Tseng, K.H., Chuang, C.P., Yeh, C.W., Chen, K.D., Lee, S.C., and Yung, B.Y. (2007). Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation. EMBO Rep 8, 394-400. Luchetti, F., Burattini, S., Ferri, P., Papa, S., and Falcieri, E. (2002). Actin involvement in apoptotic chromatin changes of hemopoietic cells undergoing hyperthermia. Apoptosis 7, 143-152. Maison, C., Bailly, D., Peters, A.H., Quivy, J.P., Roche, D., Taddei, A., Lachner, M., Jenuwein, T., and Almouzni, G. (2002). Higher-order structure in pericentric heterochromatin involves a distinct pattern of histone modification and an RNA component. Nature genetics 30, 329-334. Mamnun, Y.M., Katayama, S., and Toda, T. (2006). Fission yeast Mcl1 interacts with SCF(Pof3) and is required for centromere formation. Biochemical and biophysical research communications 350, 125-130. Martens, J.H., O'Sullivan, R.J., Braunschweig, U., Opravil, S., Radolf, M., Steinlein, P., and Jenuwein, T. (2005). The profile of repeat-associated histone lysine methylation states in the mouse epigenome. EMBO J 24, 800-812. Martini, E., Roche, D.M., Marheineke, K., Verreault, A., and Almouzni, G. (1998). Recruitment of phosphorylated chromatin assembly factor 1 to chromatin after UV irradiation of human cells. The Journal of cell biology 143, 563-575. Maydanovych, O., and Beal, P.A. (2006). Breaking the central dogma by RNA editing. Chem Rev 106, 3397-3411. Meltzer, M., Long, K., Nie, Y., Gupta, M., Yang, J., and Montano, M. (2010). The RNA editor gene ADAR1 is induced in myoblasts by inflammatory ligands and buffers stress response. Clin Transl Sci 3, 73-80. Moazed, D. (2009). Small RNAs in transcriptional gene silencing and genome defence. Nature 457, 413-420. Morris, C.A., and Moazed, D. (2007). Centromere assembly and propagation. Cell 128, 647-650. Murchison, E.P., Partridge, J.F., Tam, O.H., Cheloufi, S., and Hannon, G.J. (2005). Characterization of Dicer-deficient murine embryonic stem cells. Proc Natl Acad Sci U S A 102, 12135-12140. Natsume, T., Tsutsui, Y., Sutani, T., Dunleavy, E.M., Pidoux, A.L., Iwasaki, H., Shirahige, K., Allshire, R.C., and Yamao, F. (2008). A DNA polymerase alpha accessory protein, Mcl1, is required for propagation of centromere structures in fission yeast. PloS one 3, e2221. Nishikura, K., Yoo, C., Kim, U., Murray, J.M., Estes, P.A., Cash, F.E., and Liebhaber, S.A. (1991). Substrate specificity of the dsRNA unwinding/modifying activity. EMBO J 10, 3523-3532. Papait, R., Pistore, C., Grazini, U., Babbio, F., Cogliati, S., Pecoraro, D., Brino, L., Morand, A.L., Dechampesme, A.M., Spada, F., et al. (2008). The PHD domain of Np95 (mUHRF1) is involved in large-scale reorganization of pericentromeric heterochromatin. Mol Biol Cell 19, 3554-3563. Papait, R., Pistore, C., Negri, D., Pecoraro, D., Cantarini, L., and Bonapace, I.M. (2007). Np95 is implicated in pericentromeric heterochromatin replication and in major satellite silencing. Mol Biol Cell 18, 1098-1106. Patrone, G., Puppo, F., Cusano, R., Scaranari, M., Ceccherini, I., Puliti, A., and Ravazzolo, R. (2000). Nuclear run-on assay using biotin labeling, magnetic bead capture and analysis by fluorescence-based RT-PCR. Biotechniques 29, 1012-1014, 1016-1017. Patterson, J.B., and Samuel, C.E. (1995). Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase. Mol Cell Biol 15, 5376-5388. Patterson, J.B., Thomis, D.C., Hans, S.L., and Samuel, C.E. (1995). Mechanism of interferon action: double-stranded RNA-specific adenosine deaminase from human cells is inducible by alpha and gamma interferons. Virology 210, 508-511. Perry, R.L., Parker, M.H., and Rudnicki, M.A. (2001). Activated MEK1 binds the nuclear MyoD transcriptional complex to repress transactivation. Mol Cell 8, 291-301. Perry, R.L., and Rudnick, M.A. (2000). Molecular mechanisms regulating myogenic determination and differentiation. Front Biosci 5, D750-767. Petronczki, M., Chwalla, B., Siomos, M.F., Yokobayashi, S., Helmhart, W., Deutschbauer, A.M., Davis, R.W., Watanabe, Y., and Nasmyth, K. (2004). Sister-chromatid cohesion mediated by the alternative RF-CCtf18/Dcc1/Ctf8, the helicase Chl1 and the polymerase-alpha-associated protein Ctf4 is essential for chromatid disjunction during meiosis II. Journal of cell science 117, 3547-3559. Pfaller, C.K., Li, Z., George, C.X., and Samuel, C.E. (2011). Protein kinase PKR and RNA adenosine deaminase ADAR1: new roles for old players as modulators of the interferon response. Curr Opin Immunol 23, 573-582. Rudnicki, M.A., and Jaenisch, R. (1995). The MyoD family of transcription factors and skeletal myogenesis. Bioessays 17, 203-209. Saccone, V., and Puri, P.L. (2010). Epigenetic regulation of skeletal myogenesis. Organogenesis 6, 48-53. Samuel, C.E. (2001). Antiviral actions of interferons. Clin Microbiol Rev 14, 778-809, table of contents. Schaub, M., and Keller, W. (2002). RNA editing by adenosine deaminases generates RNA and protein diversity. Biochimie 84, 791-803. Segard, H.B., Moulin, S., Boumard, S., Augier de Cremiers, C., Kelly, P.A., and Finidori, J. (2003). Autocrine growth hormone production prevents apoptosis and inhibits differentiation in C2C12 myoblasts. Cell Signal 15, 615-623. Shan, Z.X., Lin, Q.X., Fu, Y.H., Deng, C.Y., Zhou, Z.L., Zhu, J.N., Liu, X.Y., Zhang, Y.Y., Li, Y., Lin, S.G., et al. (2009). Upregulated expression of miR-1/miR-206 in a rat model of myocardial infarction. Biochem Biophys Res Commun 381, 597-601. Sharif, J., Muto, M., Takebayashi, S., Suetake, I., Iwamatsu, A., Endo, T.A., Shinga, J., Mizutani-Koseki, Y., Toyoda, T., Okamura, K., et al. (2007). The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450, 908-912. Stefl, R., Xu, M., Skrisovska, L., Emeson, R.B., and Allain, F.H. (2006). Structure and specific RNA binding of ADAR2 double-stranded RNA binding motifs. Structure 14, 345-355. Sukma, M., Tohda, M., Watanabe, H., and Matsumoto, K. (2005). The mRNA expression differences of RNA editing enzymes in differentiated and undifferentiated NG108-15 cells. J Pharmacol Sci 98, 467-470. Takeshita, F., Takase, K., Tozuka, M., Saha, S., Okuda, K., Ishii, N., and Sasaki, S. (2007). Muscle creatine kinase/SV40 hybrid promoter for muscle-targeted long-term transgene expression. Int J Mol Med 19, 309-315. Tan, B.C., and Lee, S.C. (2004). Nek9, a novel FACT-associated protein, modulates interphase progression. J Biol Chem 279, 9321-9330. Tapscott, S.J. (2005). The circuitry of a master switch: Myod and the regulation of skeletal muscle gene transcription. Development 132, 2685-2695. Toth, A.M., Li, Z., Cattaneo, R., and Samuel, C.E. (2009). RNA-specific adenosine deaminase ADAR1 suppresses measles virus-induced apoptosis and activation of protein kinase PKR. J Biol Chem 284, 29350-29356. Townley-Tilson, W.H., Callis, T.E., and Wang, D. (2010). MicroRNAs 1, 133, and 206: critical factors of skeletal and cardiac muscle development, function, and disease. Int J Biochem Cell Biol 42, 1252-1255. van de Corput, M.P., and Grosveld, F.G. (2001). Fluorescence in situ hybridization analysis of transcript dynamics in cells. Methods 25, 111-118. Wang, Q., Khillan, J., Gadue, P., and Nishikura, K. (2000). Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science 290, 1765-1768. Wang, Q., Zhang, Z., Blackwell, K., and Carmichael, G.G. (2005). Vigilins bind to promiscuously A-to-I-edited RNAs and are involved in the formation of heterochromatin. Curr Biol 15, 384-391. Williams, D.R., and McIntosh, J.R. (2002). mcl1+, the Schizosaccharomyces pombe homologue of CTF4, is important for chromosome replication, cohesion, and segregation. Eukaryotic cell 1, 758-773. Williams, D.R., and McIntosh, J.R. (2005). Mcl1p is a polymerase alpha replication accessory factor important for S-phase DNA damage survival. Eukaryot Cell 4, 166-177. Wright, J.H., Munar, E., Jameson, D.R., Andreassen, P.R., Margolis, R.L., Seger, R., and Krebs, E.G. (1999). Mitogen-activated protein kinase kinase activity is required for the G(2)/M transition of the cell cycle in mammalian fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 96, 11335-11340. Xu, H., Boone, C., and Brown, G.W. (2007). Genetic Dissection of Parallel Sister Chromatid Cohesion Pathways. Genetics. Yaffe, D., and Saxel, O. (1977). Serial passaging and differentiation of myogenic cells isolated from dystrophic mouse muscle. Nature 270, 725-727. Yoshizawa-Sugata, N., and Masai, H. (2009). Roles of human AND-1 in chromosome transactions in S phase. J Biol Chem 284, 20718-20728. Zamai, L., Burattini, S., Luchetti, F., Canonico, B., Ferri, P., Melloni, E., Gonelli, A., Guidotti, L., Papa, S., and Falcieri, E. (2004). In vitro apoptotic cell death during erythroid differentiation. Apoptosis 9, 235-246. Zhang, P., Wong, C., Liu, D., Finegold, M., Harper, J.W., and Elledge, S.J. (1999). p21(CIP1) and p57(KIP2) control muscle differentiation at the myogenin step. Genes Dev 13, 213-224. Zhu, W., Ukomadu, C., Jha, S., Senga, T., Dhar, S.K., Wohlschlegel, J.A., Nutt, L.K., Kornbluth, S., and Dutta, A. (2007). Mcm10 and And-1/CTF4 recruit DNA polymerase alpha to chromatin for initiation of DNA replication. Genes Dev 21, 2288-2299. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16522 | - |
| dc.description.abstract | WDHD1調控著絲點沉默路徑之後轉錄階段
著絲點是一個高度特化的染色體要素，對於染色體在有絲分裂時的分離扮演很重要的角色。我們新近的努力發現一個具有WD40-domain和 HMG-domain蛋白, WDHD1, 是個不可缺的與著絲點異染色質(centromeric heterochromatin)結合之蛋白。我們的研究也發現這個蛋白和著絲點的沉默(centromere silencing) 以及異染色質結構的穩定有關。抑制WDHD1 蛋白表現會改變與這個染色質區域相關的表觀基因標誌(epigenetic marker)之表達模式。因此，這樣的結果會破壞著絲點上之異染色質狀態, 進一步造成有絲分裂的損壞。更進一步的，我們也探討了WDHD1在其中所扮演的機制，結果發現WDHD1對於著絲點區域之DNA衛星重複序列(satellite repeats)所製造出來的非編碼小RNAs (non-coding RNAs) 的生成扮演非常重要的角色。這樣的過程可能是藉由穩定Dicer和著絲點RNA的結合，而經由後轉錄模式的調控來逹成。因此，這些結論表明了WDHD1可能是個參與在經由RNA調控表觀遺傳的機制中之重要因子,使維持著絲點完整結構的。 ADAR1調控C2C12成肌細胞之肌生成作用 腺苷脫氨酶1(ADAR1)會催化雙股RNA上的腺苷(adenosine) (A)去胺基成為次黄嘌呤核苷(inosine) (I)。已知ADAR1具有兩個都有RNA編輯功能的同工型(isofroms)，一個是分子量150kDa的干擾素(interferon)誘導表現的ADAR1 p150，另一個是持續表現的ADAR1 p110。兩者都可以位在細胞核，只有p150能位在細胞質。A變成I的RNA編輯作用不只影響了RNA轉譯成蛋白質的密碼子或是其結構，也調控了反轉錄轉位子(retrotransposons)和基因的沉默(gene silencing)。在這個研究中，我們確認在骨骼肌成肌作用之調控中ADAR1的新穎生物作用。我們觀察骨骼肌成肌細胞C2C12在由成肌細胞變成肌小管(myotube)的分化過程中ADAR1的表現。在細胞聚滿(cell confluence)和分化初期ADAR p150會短暫的增加，並且兩種ADAR1的表現在隨後形成肌小管時都減少。然而，我們發現分化過程中ADAR1 p150的短暫增加是由於干擾素調控之反應片段Interferon stimulated response element (ISRE)所影響的干擾素訊息傳導路徑造成，並且隨後在分化的過程中由MyoD抑制其表現。有趣地，抑制ADAR1或是過量表現其起催化作用的區域(catalytic domain)突變的蛋白質造成成肌作用中的指標蛋白質myogenin (MyoG)和myosin heavy chain (MHC)的表現減少，說明了在細胞核中ADAR1 p110所調控的RNA編輯作用在早期成肌作用中的重要性。另外，ADAR1 p150在分化早期的作用可能是參與調節PKR所影響的細胞程式凋亡(apoptosis)。然後我們證實在分化後期ADAR1蛋白質表現減少是由於miR-1/206所引起的抑制作用。然而，在分化後期異常的ADAR1過度表現則會造成不正常的肌小管形成，更進一步指出在成肌過程中ADAR1的階段性特殊作用。總而言之，我的們結果指出在這過程中ADAR1所參與的調控，可能藉由編輯未知的轉錄本，此轉錄本對於預定的骨骼肌成肌作用之發展是必需的。 | zh_TW |
| dc.description.abstract | WDHD1 modulates the post-transcriptional step of the centromeric silencing pathway
The centromere is a highly specialized chromosomal element that is essential for chromosome segregation during mitosis. Centromere integrity must therefore be properly preserved and is strictly dependent upon the establishment and maintenance of surrounding chromatin structure. Here we identify WDHD1, a WD40-domain and HMG-domain containing protein, as a key regulator of centromere function. We show that WDHD1 associates with centromeres in a cell cycle-dependent manner, coinciding with mid-to-late S phase. WDHD1 down-regulation compromises HP1a localization to pericentric heterochromatin and leads to altered expression of epigenetic markers associated with this chromatin region. As a consequence, such reduced epigenetic silencing is manifested in disrupted heterochromatic state of the centromere and a defective mitosis. Moreover, we demonstrate that a possible underlying mechanism of WDHD1’s involvement lies in the proper generation of the small non-coding RNAs encoded by the centromeric satellite repeats. This role is mediated at the post-transcriptional level and likely through stabilizing Dicer association with centromeric RNA. Collectively, these findings suggest that WDHD1 may be a critical component of the RNA-dependent epigenetic control mechanism that sustains centromere integrity and genomic stability. ADAR1 regulates the myogenic program in C2C12 myoblast ADAR1 (adenosine deaminase acting on RNA 1) catalyzes the deamination of adenosine to inosine on RNA molecules of double stranded structure. Two isofroms of ADAR1 are known, both of which possess RNA-editing activity: an interferon (IFN) inducible 150 kDa protein (p150) and a constitutively expressed amino-terminally truncated 110 kDa protein (p110). The p150 isoform is found in both the cytoplasm and nucleus, while the p110 protein is localized predominantly in the nucleus. A-to-I RNA editing not only affects targeted transcripts by altering the sequence and/or structure of the encoded products, but also serves to regulate retrotransposons and gene silencing. In this study, we identified a novel aspect of biological function of ADAR1 in the regulation of skeletal myogenesis. We have investigated ADAR1 expression during myoblasts–myotubes differentiation in myoblast cell line C2C12: ADAR1 p150 expression transiently increased during cell confluence and initial differentiation process, whereas the expression of both ADAR1 forms dropped in the differentiated myotubes. Furthermore, we discovered that ADRA1 p150 transient up-regulation in early differentiation is mediated by the IFN signaling pathway-associated interferon stimulated response element (ISRE) and subsequently repressed by the myogenic transcription factor MyoD. Intriguingly, knockdown of ADAR1 or overexpression of a catalytic mutant reduced the expression of myogenesis-associated markers, demonstrating the significance of ADAR1 p110-mediated nuclear RNA editing in the early myogenic program. On the other hand, the function of ADAR1 p150 in early stage of differentiation possibly lies in the regulation of PKR-mediated apoptosis. Next, we demonstrated that in the late stage of myogenesis, miR-1/206-mediated inhibition facilitated the down-regulation of ADAR1 proteins. However, ectopic ADAR1 over-expression at this stage caused abnormal myotube formation, further implying stage-specific functions of ADAR1 in the myogenic process. Taken together, our results pointed to the scenario that ARAR1-mediated regulation, possibly through editing of as yet unknown transcripts, is essential for scheduled progression of skeletal myogenesis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-07T18:18:56Z (GMT). No. of bitstreams: 1 ntu-101-D96448004-1.pdf: 2614085 bytes, checksum: 31502feecf126734e1a4af9be2e30cdb (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 論文口試委員會審定書 i
摘要 ii Abstract iv Introduction 1 Centromere and RNAi-mediated heterochromatin assembly 1 WDHD1 2 Adenosine to inosine RNA editing 3 Skeletal myogenesis 6 Materials and Methods 8 Cell culture and transfection 8 Cell cycle analysis and inhibitor treatment 8 Indirect immunofluorescence and confocal microscopy 9 Cell lysate preparation 10 Western blot analysis and immunoprecipitation 10 Chromatin immunopricipitation (ChIP) 11 Real-time PCR 11 RNA isolation and reverse transcription-PCR (RT-PCR) 12 Northern blot analysis 12 Nuclease accessibility assay 13 Methylation-sensitive restriction analysis 13 Nuclear run-on assay 14 RNA pull-down assay 15 RNA immunoprecipitation 16 RNA in situ hybridization 17 Promoter and 3’UTR reporter constructs, mutagenesis, and luciferase reporter assay 18 Synthetic microRNA mimics 19 Sequence alignments and microRNA target prediction 19 Over-expression and ectopic expression constructs 20 Bromodeoxyuridine (BrdU) ELISA cell proliferation assay 20 Fusion index 20 Results 22 Part 1: WDHD1 22 Abrogation of WDHD1 expression alters the post-transcriptional processing of the centromere-encoded RNA transcripts 22 WDHD1 associates with the centromere-encoded RNA transcripts 24 WDHD1 is important for maintaining centromeric epigenetic markers 25 Heterochromatin structural alteration in the absence of WDHD1 26 Part 2: ADAR1 28 The expression profile of ADAR1 during myogenic differentiation 28 ADAR1 is necessary for scheduled progression of myogenic program 29 The transcription of inducible ADAR1 PA is mediated by the upstream interferon-responsive ISRE and repressed by MyoD 30 ADAR1 p150 regulates apoptosis of myoblasts during early myogenesis 32 ADAR1 expression in differentiated myotubes is down-regulated by myomiR’s miR-1 and miR-206 35 Ectopic expression of ADAR1 abrogates the myotube fusion of C2C12 myoblast 37 Discussion 39 WDHD1 modulates the post-transcriptional step of centromeric silencing pathway 39 ADAR1 regulates the myogenic program in C2C12 myoblasts 40 Figures 44 Figure 1. Dynamic patterns of WDHD1 subnuclear localization during S phase 44 Figure 2. Characterization of the molecular determinants underlying WDHD1’s centromeric localization 47 Figure 3. Roles of WDHD1 in the expression of centromeric repeat non-coding RNA 49 Figure 4. WDHD1 associates with the centromere-encoded RNA transcripts 51 Figure 5. Loss of heterochromatic features at the centromere in the absence of WDHD1 53 Figure 6. Down-regulation of WDHD1 leads to cell cycle progression deficiencies attributable to defective centromere 55 Figure 7. Expression of the PCT homologous small RNA fragments is Dicer-dependent 57 Figure 8. Loss of WDHD1 does not alter the nuclear distribution of centromeric RNA transcripts 58 Figure 9. The expression profile of ADAR1 during myogenesis 59 Figure 10. ADAR1 positively regulates skeletal muscle differentiation 61 Figure 11. The over-expression of ADAR1 in C2C12 myoblasts 62 Figure 12. The transcription regulation of inducible Adar1 PA promoter during myogenesis 64 Figure 13. MyoD negatively regulates the transcription of ADAR1 PA promoter 66 Figure 14. The expression profile of apoptosis-related factors during C2C12 myoblast differentiation 67 Figure 15. The anti-apoptotic function of ADAR1 p150 during initial differentiation 69 Figure 16. miR-1 and miR-206 are up-regulated and target the ADAR1 3’UTR in myoblast differentiation 72 Figure 17. The down-regulation of ADAR1 is important for myotube formation 73 References 75 | |
| dc.language.iso | en | |
| dc.subject | 肌生成作用 | zh_TW |
| dc.subject | 表關遺傳 | zh_TW |
| dc.subject | epigentics | en |
| dc.subject | myogenesis | en |
| dc.subject | ADAR1 | en |
| dc.subject | WDHD1 | en |
| dc.title | 探討後轉錄因子WDHD1和ADAR1在細胞生長及分化中之角色 | zh_TW |
| dc.title | Epigenetic regulation of cell growth and differentiation by post-transcriptional regulators WDHD1 and ADAR1 | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 譚賢明 | |
| dc.contributor.oralexamcommittee | 李芳仁,譚婉玉,張?仁 | |
| dc.subject.keyword | 表關遺傳,肌生成作用, | zh_TW |
| dc.subject.keyword | WDHD1,ADAR1,epigentics,myogenesis, | en |
| dc.relation.page | 84 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2012-02-01 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
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