請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/66826完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 蔡懷寬(Huai-Kuang Tsai) | |
| dc.contributor.author | Sufeng Chiang | en |
| dc.contributor.author | 江蘇峰 | zh_TW |
| dc.date.accessioned | 2021-06-17T01:09:01Z | - |
| dc.date.available | 2021-02-04 | |
| dc.date.copyright | 2020-02-04 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2020-01-21 | |
| dc.identifier.citation | Adem, J., Hamalainen, A., Ropponen, A., Eeva, J., Eray, M., Nuutinen, U., & Pelkonen, J. (2015). ERK1/2 has an essential role in B cell receptor- and CD40-induced signaling in an in vitro model of germinal center B cell selection. Mol Immunol, 67(2 Pt B), 240-247. doi:10.1016/j.molimm.2015.05.017
Alon, U. (2007). An introduction to systems biology : design principles of biological circuits. 2(4), 19. Boca Raton, FL: Chapman & Hall/CRC. Ashall, L., Horton, C. A., Nelson, D. E., Paszek, P., Harper, C. V., Sillitoe, K., . . . White, M. R. (2009). Pulsatile stimulation determines timing and specificity of NF-kappaB-dependent transcription. Science, 324(5924), 242-246. doi:10.1126/science.1164860 Avery, D. T., Deenick, E. K., Ma, C. S., Suryani, S., Simpson, N., Chew, G. Y., . . . Tangye, S. G. (2010). B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J Exp Med, 207(1), 155-171. doi:10.1084/jem.20091706 Banks, C. A., Boanca, G., Lee, Z. T., Eubanks, C. G., Hattem, G. L., Peak, A., . . . Washburn, M. P. (2016). TNIP2 is a Hub Protein in the NF-kappaB Network with Both Protein and RNA Mediated Interactions. Mol Cell Proteomics, 15(11), 3435-3449. doi:10.1074/mcp.M116.060509 Bannish, G., Fuentes-Panana, E. M., Cambier, J. C., Pear, W. S., & Monroe, J. G. (2001). Ligand-independent signaling functions for the B lymphocyte antigen receptor and their role in positive selection during B lymphopoiesis. J Exp Med, 194(11), 1583-1596. Berg, J. M., Tymoczko, J. L., Gatto, G. J., & Stryer, L. (2015). Biochemistry Eighth edition. ed.). 8(4), 230. New York: W.H. Freeman & Company, a Macmillan Education Imprint. Bintu, L., Buchler, N. E., Garcia, H. G., Gerland, U., Hwa, T., Kondev, J., . . . Phillips, R. (2005). Transcriptional regulation by the numbers: applications. Curr Opin Genet Dev, 15(2), 125-135. doi:10.1016/j.gde.2005.02.006 Bolger, A. M., Lohse, M., & Usadel, B. (2014). Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics, 30(15), 2114-2120. doi:10.1093/bioinformatics/btu170 Cheng, C. S., Behar, M. S., Suryawanshi, G. W., Feldman, K. E., Spreafico, R., & Hoffmann, A. (2017). Iterative Modeling Reveals Evidence of Sequential Transcriptional Control Mechanisms. Cell Syst, 4(3), 330-343 e335. doi:10.1016/j.cels.2017.01.012 Cheng, S., Hsia, C. Y., Leone, G., & Liou, H. C. (2003). Cyclin E and Bcl-xL cooperatively induce cell cycle progression in c-Rel-/- B cells. Oncogene, 22(52), 8472-8486. doi:10.1038/sj.onc.1206917 Chung, J., Uchida, E., Grammer, T. C., & Blenis, J. (1997). STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol, 17(11), 6508-6516. de Alboran, I. M., O'Hagan, R. C., Gartner, F., Malynn, B., Davidson, L., Rickert, R., . . . Alt, F. W. (2001). Analysis of C-MYC function in normal cells via conditional gene-targeted mutation. Immunity, 14(1), 45-55. De, S., Zhang, B., Shih, T., Singh, S., Winkler, A., Donnelly, R., & Barnes, B. J. (2017). B Cell-Intrinsic Role for IRF5 in TLR9/BCR-Induced Human B Cell Activation, Proliferation, and Plasmablast Differentiation. Front Immunol, 8, 1938. doi:10.3389/fimmu.2017.01938 Derudder, E., Cadera, E. J., Vahl, J. C., Wang, J., Fox, C. J., Zha, S., . . . Rajewsky, K. (2009). Development of immunoglobulin lambda-chain-positive B cells, but not editing of immunoglobulin kappa-chain, depends on NF-kappaB signals. Nat Immunol, 10(6), 647-654. doi:10.1038/ni.1732 Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., . . . Gingeras, T. R. (2013). STAR: ultrafast universal RNA-seq aligner. Bioinformatics, 29(1), 15-21. doi:10.1093/bioinformatics/bts635 Dong, C., Davis, R. J., & Flavell, R. A. (2002). MAP kinases in the immune response. Annu Rev Immunol, 20, 55-72. doi:10.1146/annurev.immunol.20.091301.131133 Estrada, J., Wong, F., DePace, A., & Gunawardena, J. (2016). Information Integration and Energy Expenditure in Gene Regulation. Cell, 166(1), 234-244. doi:10.1016/j.cell.2016.06.012 Friedman, J., Hastie, T., & Tibshirani, R. (2010). Regularization Paths for Generalized Linear Models via Coordinate Descent. J Stat Softw, 33(1), 1-22. Gallo, L. H., Meyer, A. N., Motamedchaboki, K., Nelson, K. N., Haas, M., & Donoghue, D. J. (2014). Novel Lys63-linked ubiquitination of IKKbeta induces STAT3 signaling. Cell Cycle, 13(24), 3964-3976. doi:10.4161/15384101.2014.988026 Garcia-Alonso, L., Iorio, F., Matchan, A., Fonseca, N., Jaaks, P., Peat, G., . . . Saez-Rodriguez, J. (2018). Transcription Factor Activities Enhance Markers of Drug Sensitivity in Cancer. Cancer Res, 78(3), 769-780. doi:10.1158/0008-5472.CAN-17-1679 Gerondakis, S., Grumont, R. J., & Banerjee, A. (2007). Regulating B-cell activation and survival in response to TLR signals. Immunol Cell Biol, 85(6), 471-475. doi:10.1038/sj.icb.7100097 Ghosh, S., May, M. J., & Kopp, E. B. (1998). NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol, 16, 225-260. doi:10.1146/annurev.immunol.16.1.225 Gitter, A., Carmi, M., Barkai, N., & Bar-Joseph, Z. (2013). Linking the signaling cascades and dynamic regulatory networks controlling stress responses. Genome Res, 23(2), 365-376. doi:10.1101/gr.138628.112 Goodnow, C. C., Vinuesa, C. G., Randall, K. L., Mackay, F., & Brink, R. (2010). Control systems and decision making for antibody production. Nat Immunol, 11(8), 681-688. doi:10.1038/ni.1900 Grumont, R. J., Rourke, I. J., & Gerondakis, S. (1999). Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev, 13(4), 400-411. Grumont, R. J., Rourke, I. J., O'Reilly, L. A., Strasser, A., Miyake, K., Sha, W., & Gerondakis, S. (1998). B lymphocytes differentially use the Rel and nuclear factor kappaB1 (NF-kappaB1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. J Exp Med, 187(5), 663-674. Grumont, R. J., Strasser, A., & Gerondakis, S. (2002). B cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction of Rel/NF-kappaB regulated c-myc transcription. Mol Cell, 10(6), 1283-1294. Gupta, S., & Davis, R. J. (1994). MAP kinase binds to the NH2-terminal activation domain of c-Myc. FEBS Lett, 353(3), 281-285. Ha, S. H., & Ferrell, J. E., Jr. (2016). Thresholds and ultrasensitivity from negative cooperativity. Science, 352(6288), 990-993. doi:10.1126/science.aad5937 Hacker, H., & Karin, M. (2006). Regulation and function of IKK and IKK-related kinases. Sci STKE, 2006(357), re13. doi:10.1126/stke.3572006re13 Han, A., Saijo, K., Mecklenbrauker, I., Tarakhovsky, A., & Nussenzweig, M. C. (2003). Bam32 links the B cell receptor to ERK and JNK and mediates B cell proliferation but not survival. Immunity, 19(4), 621-632. Hertz, G. Z., & Stormo, G. D. (1999). Identifying DNA and protein patterns with statistically significant alignments of multiple sequences. Bioinformatics, 15(7-8), 563-577. Hindmarsh, A. C., Brown, P. N., Grant, K. E., Lee, S. L., Serban, R., Shumaker, D. E., & Woodward, C. S. (2005). SUNDIALS: Suite of nonlinear and differential/algebraic equation solvers. ACM Trans. Math. Softw., 31(3), 363-396. doi:10.1145/1089014.1089020 Huang, S. S., Clarke, D. C., Gosline, S. J., Labadorf, A., Chouinard, C. R., Gordon, W., . . . Fraenkel, E. (2013). Linking proteomic and transcriptional data through the interactome and epigenome reveals a map of oncogene-induced signaling. PLoS Comput Biol, 9(2), e1002887. doi:10.1371/journal.pcbi.1002887 Huang, S. S., & Fraenkel, E. (2009). Integrating proteomic, transcriptional, and interactome data reveals hidden components of signaling and regulatory networks. Sci Signal, 2(81), ra40. doi:10.1126/scisignal.2000350 Ihaka, R., & Gentleman, R. (1996). R: A Language for Data Analysis and Graphics. Journal of Computational and Graphical Statistics, 5(3), 299-314. doi:10.2307/1390807 Irizarry, R. A., Hobbs, B., Collin, F., Beazer-Barclay, Y. D., Antonellis, K. J., Scherf, U., & Speed, T. P. (2003). Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics, 4(2), 249-264. doi:10.1093/biostatistics/4.2.249 Jin, Z., Gao, F., Flagg, T., & Deng, X. (2004). Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone promotes functional cooperation of Bcl2 and c-Myc through phosphorylation in regulating cell survival and proliferation. J Biol Chem, 279(38), 40209-40219. doi:10.1074/jbc.M404056200 Kaisho, T., Takeda, K., Tsujimura, T., Kawai, T., Nomura, F., Terada, N., & Akira, S. (2001). IkappaB kinase alpha is essential for mature B cell development and function. J Exp Med, 193(4), 417-426. Kataoka, K., Handa, H., & Nishizawa, M. (2001). Induction of cellular antioxidative stress genes through heterodimeric transcription factor Nrf2/small Maf by antirheumatic gold(I) compounds. J Biol Chem, 276(36), 34074-34081. doi:10.1074/jbc.M105383200 Kenter, A. L., Wuerffel, R., Dominguez, C., Shanmugam, A., & Zhang, H. (2004). Mapping of a functional recombination motif that defines isotype specificity for mu-->gamma3 switch recombination implicates NF-kappaB p50 as the isotype-specific switching factor. J Exp Med, 199(5), 617-627. doi:10.1084/jem.20031935 Kislinger, T., Cox, B., Kannan, A., Chung, C., Hu, P., Ignatchenko, A., . . . Emili, A. (2006). Global survey of organ and organelle protein expression in mouse: combined proteomic and transcriptomic profiling. Cell, 125(1), 173-186. doi:10.1016/j.cell.2006.01.044 Koncz, G., Bodor, C., Kovesdi, D., Gati, R., & Sarmay, G. (2002). BCR mediated signal transduction in immature and mature B cells. Immunol Lett, 82(1-2), 41-49. Kramer, A., Green, J., Pollard, J., Jr., & Tugendreich, S. (2014). Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics, 30(4), 523-530. doi:10.1093/bioinformatics/btt703 Kurosaki, T., Shinohara, H., & Baba, Y. (2010). B cell signaling and fate decision. Annu Rev Immunol, 28, 21-55. doi:10.1146/annurev.immunol.021908.132541 Lam, L. T., Davis, R. E., Ngo, V. N., Lenz, G., Wright, G., Xu, W., . . . Staudt, L. M. (2008). Compensatory IKKalpha activation of classical NF-kappaB signaling during IKKbeta inhibition identified by an RNA interference sensitization screen. Proc Natl Acad Sci U S A, 105(52), 20798-20803. doi:10.1073/pnas.0806491106 Lan, A., Smoly, I. Y., Rapaport, G., Lindquist, S., Fraenkel, E., & Yeger-Lotem, E. (2011). ResponseNet: revealing signaling and regulatory networks linking genetic and transcriptomic screening data. Nucleic Acids Res, 39(Web Server issue), W424-429. doi:10.1093/nar/gkr359 LeBien, T. W., & Tedder, T. F. (2008). B lymphocytes: how they develop and function. Blood, 112(5), 1570-1580. doi:10.1182/blood-2008-02-078071 Li, B., & Dewey, C. N. (2011). RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics, 12, 323. doi:10.1186/1471-2105-12-323 Limnander, A., Depeille, P., Freedman, T. S., Liou, J., Leitges, M., Kurosaki, T., . . . Weiss, A. (2011). STIM1, PKC-delta and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nat Immunol, 12(5), 425-433. doi:10.1038/ni.2016 Lin, E. Y., Orlofsky, A., Wang, H. G., Reed, J. C., & Prystowsky, M. B. (1996). A1, a Bcl-2 family member, prolongs cell survival and permits myeloid differentiation. Blood, 87(3), 983-992. Litman, G. W., Rast, J. P., & Fugmann, S. D. (2010). The origins of vertebrate adaptive immunity. Nat Rev Immunol, 10(8), 543-553. doi:10.1038/nri2807 Lo, R. K., Wise, H., & Wong, Y. H. (2006). Prostacyclin receptor induces STAT1 and STAT3 phosphorylations in human erythroleukemia cells: a mechanism requiring PTX-insensitive G proteins, ERK and JNK. Cell Signal, 18(3), 307-317. doi:10.1016/j.cellsig.2005.05.001 Ma, W., Trusina, A., El-Samad, H., Lim, W. A., & Tang, C. (2009). Defining network topologies that can achieve biochemical adaptation. Cell, 138(4), 760-773. doi:10.1016/j.cell.2009.06.013 Merchant, A. A., Singh, A., Matsui, W., & Biswal, S. (2011). The redox-sensitive transcription factor Nrf2 regulates murine hematopoietic stem cell survival independently of ROS levels. Blood, 118(25), 6572-6579. doi:10.1182/blood-2011-05-355362 Mertins, P., Przybylski, D., Yosef, N., Qiao, J., Clauser, K., Raychowdhury, R., . . . Chevrier, N. (2017). An Integrative Framework Reveals Signaling-to-Transcription Events in Toll-like Receptor Signaling. Cell Rep, 19(13), 2853-2866. doi:10.1016/j.celrep.2017.06.016 Morales, A. V., Yasuda, Y., & Ish-Horowicz, D. (2002). Periodic Lunatic fringe expression is controlled during segmentation by a cyclic transcriptional enhancer responsive to notch signaling. Dev Cell, 3(1), 63-74. Nagashima, T., Shimodaira, H., Ide, K., Nakakuki, T., Tani, Y., Takahashi, K., . . . Hatakeyama, M. (2007). Quantitative transcriptional control of ErbB receptor signaling undergoes graded to biphasic response for cell differentiation. J Biol Chem, 282(6), 4045-4056. doi:10.1074/jbc.M608653200 Nakakuki, T., Birtwistle, M. R., Saeki, Y., Yumoto, N., Ide, K., Nagashima, T., . . . Kholodenko, B. N. (2010). Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics. Cell, 141(5), 884-896. doi:10.1016/j.cell.2010.03.054 Niiro, H., & Clark, E. A. (2002). Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol, 2(12), 945-956. doi:10.1038/nri955 Noble, W. S. (2009). How does multiple testing correction work? Nat Biotechnol, 27(12), 1135-1137. doi:10.1038/nbt1209-1135 Noh, H., Shoemaker, J. E., & Gunawan, R. (2018). Network perturbation analysis of gene transcriptional profiles reveals protein targets and mechanism of action of drugs and influenza A viral infection. Nucleic Acids Res, 46(6), e34. doi:10.1093/nar/gkx1314 Oeckinghaus, A., Hayden, M. S., & Ghosh, S. (2011). Crosstalk in NF-kappaB signaling pathways. Nat Immunol, 12(8), 695-708. doi:10.1038/ni.2065 Osmanbeyoglu, H. U., Pelossof, R., Bromberg, J. F., & Leslie, C. S. (2014). Linking signaling pathways to transcriptional programs in breast cancer. Genome Res, 24(11), 1869-1880. doi:10.1101/gr.173039.114 Osmanbeyoglu, H. U., Toska, E., Chan, C., Baselga, J., & Leslie, C. S. (2017). Pancancer modelling predicts the context-specific impact of somatic mutations on transcriptional programs. Nat Commun, 8, 14249. doi:10.1038/ncomms14249 Pahl, H. L. (1999). Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene, 18(49), 6853-6866. doi:10.1038/sj.onc.1203239 Pasparakis, M., Schmidt-Supprian, M., & Rajewsky, K. (2002). IkappaB kinase signaling is essential for maintenance of mature B cells. J Exp Med, 196(6), 743-752. Pelossof, R., Singh, I., Yang, J. L., Weirauch, M. T., Hughes, T. R., & Leslie, C. S. (2015). Affinity regression predicts the recognition code of nucleic acid-binding proteins. Nat Biotechnol, 33(12), 1242-1249. doi:10.1038/nbt.3343 Pore, D., Parameswaran, N., Matsui, K., Stone, M. B., Saotome, I., McClatchey, A. I., . . . Gupta, N. (2013). Ezrin tunes the magnitude of humoral immunity. J Immunol, 191(8), 4048-4058. doi:10.4049/jimmunol.1301315 Remenyi, A., Scholer, H. R., & Wilmanns, M. (2004). Combinatorial control of gene expression. Nat Struct Mol Biol, 11(9), 812-815. doi:10.1038/nsmb820 Richards, J. D., Dave, S. H., Chou, C. H., Mamchak, A. A., & DeFranco, A. L. (2001). Inhibition of the MEK/ERK signaling pathway blocks a subset of B cell responses to antigen. J Immunol, 166(6), 3855-3864. Santos, S. D., Verveer, P. J., & Bastiaens, P. I. (2007). Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. Nat Cell Biol, 9(3), 324-330. doi:10.1038/ncb1543 Satpathy, S., Wagner, S. A., Beli, P., Gupta, R., Kristiansen, T. A., Malinova, D., . . . Choudhary, C. (2015). Systems-wide analysis of BCR signalosomes and downstream phosphorylation and ubiquitylation. Mol Syst Biol, 11(6), 810. doi:10.15252/msb.20145880 Seda, V., & Mraz, M. (2015). B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol, 94(3), 193-205. doi:10.1111/ejh.12427 Senftleben, U., Cao, Y., Xiao, G., Greten, F. R., Krahn, G., Bonizzi, G., . . . Karin, M. (2001). Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science, 293(5534), 1495-1499. doi:10.1126/science.1062677 Shinohara, H., Inoue, K., Yumoto, N., Nagashima, T., & Okada-Hatakeyama, M. (2016). Stimulus-Dependent Inhibitor of Apoptosis Protein Expression Prolongs the Duration of B Cell Signalling. Sci Rep, 6, 27706. doi:10.1038/srep27706 Shinohara, H., & Kurosaki, T. (2006). Genetic analysis of B cell signaling. Subcell Biochem, 40, 145-187. doi:10.1007/978-1-4020-4896-8_10 Shinohara, H., Maeda, S., Watarai, H., & Kurosaki, T. (2007). IkappaB kinase beta-induced phosphorylation of CARMA1 contributes to CARMA1 Bcl10 MALT1 complex formation in B cells. J Exp Med, 204(13), 3285-3293. doi:10.1084/jem.20070379 Siepel, A., Bejerano, G., Pedersen, J. S., Hinrichs, A. S., Hou, M., Rosenbloom, K., . . . Haussler, D. (2005). Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res, 15(8), 1034-1050. doi:10.1101/gr.3715005 Somasundaram, R., Prasad, M. A., Ungerback, J., & Sigvardsson, M. (2015). Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia. Blood, 126(2), 144-152. doi:10.1182/blood-2014-12-575688 Su, T. T., Guo, B., Kawakami, Y., Sommer, K., Chae, K., Humphries, L. A., . . . Rawlings, D. J. (2002). PKC-beta controls I kappa B kinase lipid raft recruitment and activation in response to BCR signaling. Nat Immunol, 3(8), 780-786. doi:10.1038/ni823 Szklarczyk, D., Franceschini, A., Wyder, S., Forslund, K., Heller, D., Huerta-Cepas, J., . . . von Mering, C. (2015). STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res, 43(Database issue), D447-452. doi:10.1093/nar/gku1003 Tan, J. B., Xu, K., Cretegny, K., Visan, I., Yuan, J. S., Egan, S. E., & Guidos, C. J. (2009). Lunatic and manic fringe cooperatively enhance marginal zone B cell precursor competition for delta-like 1 in splenic endothelial niches. Immunity, 30(2), 254-263. doi:10.1016/j.immuni.2008.12.016 Tiacci, E., Orvietani, P. L., Bigerna, B., Pucciarini, A., Corthals, G. L., Pettirossi, V., . . . Falini, B. (2005). Tumor protein D52 (TPD52): a novel B-cell/plasma-cell molecule with unique expression pattern and Ca(2+)-dependent association with annexin VI. Blood, 105(7), 2812-2820. doi:10.1182/blood-2004-07-2630 Tummler, K., Lubitz, T., Schelker, M., & Klipp, E. (2014). New types of experimental data shape the use of enzyme kinetics for dynamic network modeling. FEBS J, 281(2), 549-571. doi:10.1111/febs.12525 Wang, K., Saito, M., Bisikirska, B. C., Alvarez, M. J., Lim, W. K., Rajbhandari, P., . . . Califano, A. (2009). Genome-wide identification of post-translational modulators of transcription factor activity in human B cells. Nat Biotechnol, 27(9), 829-839. doi:10.1038/nbt.1563 Weirauch, M. T., Yang, A., Albu, M., Cote, A. G., Montenegro-Montero, A., Drewe, P., . . . Hughes, T. R. (2014). Determination and inference of eukaryotic transcription factor sequence specificity. Cell, 158(6), 1431-1443. doi:10.1016/j.cell.2014.08.009 Yachie-Kinoshita, A., Onishi, K., Ostblom, J., Langley, M. A., Posfai, E., Rossant, J., & Zandstra, P. W. (2018). Modeling signaling-dependent pluripotency with Boolean logic to predict cell fate transitions. Mol Syst Biol, 14(1), e7952. doi:10.15252/msb.20177952 Yamazaki, T., & Kurosaki, T. (2003). Contribution of BCAP to maintenance of mature B cells through c-Rel. Nat Immunol, 4(8), 780-786. doi:10.1038/ni949 Yasuda, T., Sanjo, H., Pages, G., Kawano, Y., Karasuyama, H., Pouyssegur, J., . . . Kurosaki, T. (2008). Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion. Immunity, 28(4), 499-508. doi:10.1016/j.immuni.2008.02.015 Yeh, P. Y., Lu, Y. S., Ou, D. L., & Cheng, A. L. (2011). IkappaB kinases increase Myc protein stability and enhance progression of breast cancer cells. Mol Cancer, 10, 53. doi:10.1186/1476-4598-10-53 Zaffaroni, G., Okawa, S., Morales-Ruiz, M., & Del Sol, A. (2019). An integrative method to predict signalling perturbations for cellular transitions. Nucleic Acids Res, 47(12), e72. doi:10.1093/nar/gkz232 Zhang, N., & Gridley, T. (1998). Defects in somite formation in lunatic fringe-deficient mice. Nature, 394(6691), 374-377. doi:10.1038/28625 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/66826 | - |
| dc.description.abstract | 破解細胞用以調控基因表現的機制為解析細胞生理現象的重要拼圖之一。在調控基因表現的機制中，轉錄因子為整體調控網路的樞紐。轉錄因子可受到上游訊息傳遞途徑的活化，並藉由結合至基因中的特定位置以調控特定功能的基因表現。關於轉錄因子如何協調訊息傳遞途徑以調控基因表現的機制仍無一定論。針對此問題，過去已開發很多相關的演算法分析轉錄因子在訊息傳遞途徑中的樞紐位置與其所參與的調控網路。然而，至今尚未有研究系統性地分析轉錄因子與訊息傳遞途徑的交互作用，與其對下游基因表現的調控機制。本論文欲解開轉錄因子如何協調上游訊息傳遞途徑以調控基因表現，乃發展一整合式計算方法，分析免疫細胞的訊息傳遞蛋白質活性與高通量基因體表現資料，主要探討B細胞中IKK與ERK訊息傳遞路徑調控轉錄性反應的調控機制模型。
本研究藉由分析顯著差異表現基因、預測可能的調控轉錄因子，並進而利用親和力迴歸分析方法估計ERK與IKK訊息傳遞途徑對下游轉錄因子的交互作用。進而發現在B細胞早期活化過程中，大部分轉錄因子的活化由ERK所調控。IKK所調控的轉錄因子屬於少數，但卻在轉錄調控機制中扮演了關鍵的角色。並進一步建構轉錄調控機制的動力學模型，利用電腦模擬分析轉錄因子如何調控基因表現。模擬結果顯示ERK所調控與IKK所調控的轉錄因子間的組合調控機制可以調控多樣化的基因表現樣式以控制B細胞活化過程。本研究揭露了在B細胞早期活化過程，整合不同的訊息傳遞途徑控制轉錄因子組合調控網路是達成B細胞功能的關鍵步驟。 藉由整合線性回歸迴歸分析與建模方法，本研究闡明了B細胞活化過程中，受訊息傳遞途徑調控基因表現的調控機制。本研究成果希望能提升對細胞生理現象中，細胞外刺激與基因表現反應調控機制的認識，並強化B細胞相關研究在臨床應用上的研究基礎。本研究架構同時提供ㄧ可行的整合方法，系統性地分析轉錄因子與訊息傳遞途徑的交互作用，與其對下游基因表現的調控機制，期能應用在分析基礎細胞生理現象，並貢獻於免疫疾病，甚或癌症治療的臨床研究中。 | zh_TW |
| dc.description.abstract | Gene expression is the outcome of the hierarchical activation of signaling pathways via a tightly controlled network of interacting elements in the eukaryotic cell. Among the interacting elements, transcription factors (TFs) play an important role in the signaling pathways and often control gene expression in combinatorial fashion. However, how TFs coordinate the signals from different signaling pathways and their combinatorial control remain unclear. A number of algorithms have been developed to study the central role of TFs in the signaling pathways and regulatory networks. However, a systematic study of the interacting relationship between signaling pathways and TFs, and an explicit paradigm of transcriptional regulatory mechanism still lack yet.
In this study, the interacting relationships of TFs in ERK and IKK signaling pathways and the transcriptional regulatory mechanism of the primary response of B cells are addressed. I estimated the interacting relationship between ERK and IKK signaling pathways and TFs by using an affinity regression model. To further analyze the regulatory mechanism of TFs, I built up a kinetic model to simulate and predict how the regulating TFs would coordinate ERK and IKK to control gene expression. According to the regression analysis, I found that the majority of the regulating TFs were regulated dominantly by the ERK signaling in B cells. The simulation revealed that the combination of TFs differentially controlled by ERK and IKK contributed to the divergent gene expression patterns in orchestrating the primary B cell response. This study suggests that coordinating the differentially activated signaling proteins to recruit the proper TF combinatorial regulatory network is important to achieve the transcriptional control of the early B cell development. The key finding elucidates the underlying mechanism of the signal-dependent gene expression in the signaling pathways responsible for the B cell activation. The integrative method could be broadly applied in other stimulus-response systems. Solving the transcriptional regulatory mechanism could provide the conceptual basis for interpreting the underlying mechanism behind the cell physiology in basic cell biology studies and clinical researches. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T01:09:01Z (GMT). No. of bitstreams: 1 ntu-108-D01b48010-1.pdf: 26648371 bytes, checksum: c79f403662e6f2b406ec0a5c19db3005 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 Acknowledgments iii 摘要 v ABSTRACT vii TABLE OF CONTENTS ix LIST OF FIGURES xiii LIST OF TABLES xv CHAPTER 1 Introduction 1 1.1 Transcription factor plays as a hub coordinating the upstream signals 2 1.2 Transcription factors regulate target genes in a combinatorial fashion 3 1.3 Systematical dissection of the signal-to-transcription factor relationship 4 1.4 Identifying the function of transcription factors via molecular mechanistic models 5 1.5 Model-aided analysis of the transcriptional regulatory mechanism of stimulus-response system 6 1.6 The primary response of B cells 7 1.6.1 ERK signal transduction pathway 9 1.6.2 IKK signal transduction pathway 9 1.6.3 The distinct dynamics of ERK and IKK signals in the primary response of B cells 10 1.7 Overview of the research 11 CHAPTER 2 Materials and Methods 13 2.1 Analysis of the genome-wide gene expression data 15 2.1.1 Data processing of the microarray data of chicken B cells 15 2.1.2 Identification of the differentially expressed genes of chicken B cells 15 2.1.3 Identification of ERK- and IKK-dependent genes 16 2.2 Prediction of the regulating transcription factors 18 2.2.1 Ab initio sequence-based prediction 18 2.2.2 Prior knowledge-based refinement 20 2.3 Kinase activities of ERK and IKK of chicken B cells 20 2.4 Affinity regression model 21 2.5 Kinetic modeling and simulation 23 2.5.1 The Michaelis-Menten kinetic model for the regulatory activity of transcription factor 23 2.5.2 The graph-based gene regulation model of a pair of transcription factors 24 2.5.3 The mathematical formulation of transcription rate 27 2.5.4 Mathematical model simulation 28 2.5.5 The goodness of mathematical model fits 28 2.6 Identification of the up-regulated DEGs conserved between chicken and mouse 29 2.6.1 Data processing of the RNA-Seq data of mouse B cells 29 2.6.2 The mouse orthologous genes of the chicken DEGs 30 CHAPTER 3 Results 31 3.1 The interacting relationship of transcription factors in ERK and IKK signaling pathways 31 3.1.1 The differentially expressed genes in the primary response of B cells 31 3.1.2 The regulating transcription factors of the primary response of B cells 33 3.1.3 The interacting relationships of ERK and IKK to the regulating transcription factors 35 3.2 The transcriptional regulatory mechanism of the primary response of B cells 39 3.2.1 The signal-dependent regulatory activities of transcription factors 39 3.2.2 From transcription factors to dynamics of gene expression: considering the combinatorial control of transcription factor pairs 45 3.2.3 The transcriptional regulatory mechanism of the primary response of B cells 51 3.3 The core transcriptional regulatory network of the primary response of B cells 54 3.3.1 The assigned transcriptional regulatory modules of the DEGs conserved between chicken and mouse 54 3.3.2 The hub transcription factors 56 3.3.3 The core transcription factor module 58 CHAPTER 4 Discussions 61 4.1 ERK and IKK signal-dependent transcription factor activities 61 4.2 B cell responses are mainly controlled through the cooperative regulation between transcription factors 62 4.3 Validity of the integrative pipeline 63 4.4 Rediscovering the governing rule of stimulus-response system 65 4.5 Future works 66 REFERENCES 69 | |
| dc.language.iso | en | |
| dc.title | 利用生物資訊學方法分析受多訊息控制的基因表現之轉錄調控機制 | zh_TW |
| dc.title | Deciphering the Transcriptional Regulation of Signal-Dependent Gene Expression in Silico | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 岡田?里子(Mariko Okada) | |
| dc.contributor.oralexamcommittee | 阮雪芬(Hsueh-Fen Juan),黃宣誠(Hsuan-Cheng Huang),陳倩瑜(Chien-Yu Chen),楊立威(Lee-Wei Yang),陳昇宏(Sheng-hong Chen) | |
| dc.subject.keyword | 轉錄因子,轉錄調控機制,訊息傳遞途徑,基因表現,迴歸分析,動力學建模,電腦模擬, | zh_TW |
| dc.subject.keyword | transcription factor,regulatory mechanism,signal transduction pathway,signal-dependent gene expression,combinatorial control,regression analysis,kinetic modeling, | en |
| dc.relation.page | 86 | |
| dc.identifier.doi | 10.6342/NTU202000214 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2020-01-21 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 基因體與系統生物學學位學程 | zh_TW |
| 顯示於系所單位： | 基因體與系統生物學學位學程 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-108-1.pdf 目前未授權公開取用 | 26.02 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。