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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張茂山 | zh_TW |
| dc.contributor.advisor | Mau-Sun Chang | en |
| dc.contributor.author | 李晉毓 | zh_TW |
| dc.contributor.author | Jin-Yu Lee | en |
| dc.date.accessioned | 2024-01-26T16:23:00Z | - |
| dc.date.available | 2024-01-27 | - |
| dc.date.copyright | 2024-01-26 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-12-05 | - |
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A., Akiyama, H., & Honjo, T. (2012). The DSIF subunits Spt4 and Spt5 have distinct roles at various phases of immunoglobulin class switch recombination. PLoS Genet, 8(4), e1002675. https://doi.org/10.1371/journal.pgen.1002675 Stavnezer, J., Guikema, J. E., & Schrader, C. E. (2008). Mechanism and regulation of class switch recombination. Annu Rev Immunol, 26, 261-292. https://doi.org/10.1146/annurev.immunol.26.021607.090248 Tomoda, T., Kurashige, T., Moriki, T., Yamamoto, H., Fujimoto, S., & Taniguchi, T. (1991, Aug). Enhanced expression of poly(ADP-ribose) synthetase gene in malignant lymphoma. Am J Hematol, 37(4), 223-227. https://doi.org/10.1002/ajh.2830370402 Wang, L., Wuerffel, R., Feldman, S., Khamlichi, A. A., & Kenter, A. L. (2009, Aug 3). S region sequence, RNA polymerase II, and histone modifications create chromatin accessibility during class switch recombination. J Exp Med, 206(8), 1817-1830. https://doi.org/10.1084/jem.20081678 Ward, I. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/91410 | - |
| dc.description.abstract | PHD and RING finger domain protein 1 (PHRF1)是一種具有1649個胺基酸的E3接合酶，屬於核蛋白，過去研究指出，PHRF1藉由E3接合酶功能，將TGF-訊息傳遞路徑之抑制蛋白TG-interacting factor (TGIF)泛素化後分解，加強TGF-訊息傳遞，PHRF1亦被報導為抑癌基因，因PML-RAR造成PHRF1表現量下降將加速急性早幼粒細胞白血病(APL)病程。PHRF1可和組織蛋白H3K36me3修飾作用，並於基因損傷時藉由結合NBS1等與基因修復機制相關蛋白，加強非同源末端接合 (non-homologous end joining, NHEJ)基因修復機制，同時，PHRF1亦被發現可藉由與Rpb1作用，增加Zeb1 RNA轉錄效率及Zeb1在A549肺癌癌細胞中的表現量，進而增加癌細胞轉移能力。
本篇研究探討PHRF1在抗體類型轉換(class switch recombination)(CSR)中所扮演的角色，我們利用Crispr-Cas9技術將小鼠淋巴瘤CH12F3-2A細胞PHRF1剔除，經實驗發現PHRF1剔除造成CH12F3-2A細胞CSR效率下降，將PHRF1重新送入PHRF1剔除細胞可使CSR效率部分回升，但是經實驗分析，CH12F3-2A細胞的germline transcription (GLT)以及細胞分裂速度皆不會受到PHRF1剔除影響，同時，以Junction analysis分析CH12F3-2A細胞，發現PHRF1剔除不會影響重組基因接合部位微同源性序列長度，後續實驗利用西方墨點法分析野生型以及PHRF1剔除CH12F3-2A細胞，發現PARP1, NELF-A, NELF-D 表現量以及pS2, pS2S5修飾在 Rpb1 CTD位置的量有顯著變化，另外以電穿孔方式將PARP1送入PHRF1剔除CH12F3-2A細胞可以部份回升CSR效率。同時，本實驗亦使用帶有CD19-Cre及PHRF1基因座兩端含Cre重組酶辨識序列的小鼠，經以流式細胞儀分析小鼠骨隨及脾臟細胞，發現PHRF1基因剔除並未影響B細胞發育及分化，利用自小鼠脾臟分離之未活化的B細胞，經處理對應之細胞激素後，發現PHRF1基因剔除並未影響未活化的B細胞自IgM進行CSR轉換IgG1, IgG2b, IgG3 and IgA之效率，再以西方墨點法分析，發現PARP1及 NELF-D兩種蛋白在野生型小鼠及PHRF1基因剔除小鼠B細胞中並無表現量的差異，綜上，本研究發現PHRF1參與CH12F3-2A細胞的免疫球蛋白類型轉換機制。 | zh_TW |
| dc.description.abstract | PHD and RING finger domain protein 1(PHRF1) is an E3 ligase with 1649 amino acid. In previous reports, PHRF1 promotes TGF- signaling by ubiquitinating a TGF- signaling suppressor homeodomain repressor TG-interacting factor (TGIF). PHRF1 has also been reported to act as a tumor suppressor gene. PML-RARα protein interferes with PHRF1-mediated TGIF breakdown promotes the progression of acute promyelocytic leukemia (APL). Moreover, PHRF1 links H3K36me3 histone and NBS1 with DNA repair machinery factor under DNA damage and increases the efficacy of non-homologous end-joining (NHEJ). PHRF1 has also been reported to increase Zeb1 RNA transcription by interacting with Rpb1 and promoting the migration of A549 lung cancer cells.
This study focused on the role of PHRF1 in class switch recombination (CSR). We used Crispr-Cas9 mediated PHRF1 knockout and shRNA-silenced CH12F3-2A cells to conduct experiment. This study revealed that PHRF1 depletion decreased IgA switching. Reintroducing PHRF1 into PHRF1-depleted CH12F3-2A cells resulted in the restoration of IgA switching. PHRF1 depletion did not influence germline transcription (GLT) and cell proliferation in CH12F3-2A cells. Also, Junction analysis showed that PHRF1 depletion made no significant difference in microhomology analysis. With immunoblotting assay, we discovered that PHRF1 depletion decreased the amounts of PARP1, NELF-A, NELF-D and phosphorylation of Ser2, Ser2Ser5 of the C-terminal domain (CTD) on Rpb1. Reintroducing PARP1 into PHRF1-depleted CH12F3-2A cells resulted in a partial restoration of IgA switching. In an animal study, CD19-Cre-driven PHRF1 knockout mice showed no defect in B cell development and proliferation. However, knockout PHRF1 in mice splenic B cell did not interfere the efficacy of class switching from IgM to IgG1, IgG2b, IgG3, and IgA. The levels of PARP1 and NELF-D were not decreased in PHRF1-depleted primary splenic B cells. Our findings suggest that PHRF1 may modulate IgA switching through PARP1 in CH12F3-2A cells but not in mice. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-01-26T16:23:00Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-01-26T16:23:00Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 摘要………………………………………………………………….…. i
Abstract…………………………………………………………….…… iii Contents…………………………………………………………………... v Introduction…………………………………………………………….….1 Materials and Methods………………………………………………….…7 Results……………………………………………………………………13 Discussion………………………………………………………………...24 Reference………………………………………………………………….29 Figures…………………………………………………………………….35 Tables……………………………………………………………………..55 | - |
| dc.language.iso | en | - |
| dc.subject | 小鼠淋巴瘤細胞 | zh_TW |
| dc.subject | CH12F3-2A | zh_TW |
| dc.subject | PHRF1 | zh_TW |
| dc.subject | 免疫球蛋白類型轉換 | zh_TW |
| dc.subject | CH12F3-2A | en |
| dc.subject | PHD and RING finger domain protein 1 | en |
| dc.subject | PHRF1 | en |
| dc.subject | class switch recombination | en |
| dc.subject | CSR | en |
| dc.title | 探討PHRF1在CH12F3-2A 淋巴瘤細胞扮演促進抗體類型轉換成IgA抗體之研究 | zh_TW |
| dc.title | PHRF1 promotes the class switch recombination of IgA in CH12F3-2A cells | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-1 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 蕭超隆;張震東;黃楓婷;朱伯振 | zh_TW |
| dc.contributor.oralexamcommittee | Chiao-long Hsiao;Geen-Dong Chang;Feng-Ting Huang;Po-Chen Chu | en |
| dc.subject.keyword | 免疫球蛋白類型轉換,PHRF1,CH12F3-2A,小鼠淋巴瘤細胞, | zh_TW |
| dc.subject.keyword | PHD and RING finger domain protein 1,PHRF1,class switch recombination,CSR,CH12F3-2A, | en |
| dc.relation.page | 56 | - |
| dc.identifier.doi | 10.6342/NTU202304481 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2023-12-07 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生化科學研究所 | - |
| 顯示於系所單位： | 生化科學研究所 | |
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