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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 呂勝春 | |
dc.contributor.author | Jung-Hung Chen | en |
dc.contributor.author | 陳濬黌 | zh_TW |
dc.date.accessioned | 2021-05-17T09:15:28Z | - |
dc.date.available | 2017-09-18 | |
dc.date.available | 2021-05-17T09:15:28Z | - |
dc.date.copyright | 2012-09-18 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-08-09 | |
dc.identifier.citation | Akerman, M., H. David-Eden, et al. (2009). 'A computational approach for genome-wide mapping of splicing factor binding sites.' Genome Biol 10(3): R30.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/6629 | - |
dc.description.abstract | ADAR1為一具有脫氨活性的酵素,能將雙股RNA上與胸苷酸配對的腺苷酸進行脫氨而形成肌苷酸。由於肌苷酸結構與鳥苷酸相似,這種核苷酸序列的改變可能影響到RNA的二級結構、RNA的穩定性甚至是密碼子的組成,造成基因表現程度甚至是基因功能的改變。ADAR1包含兩種蛋白異構體,分別為ADAR1p150和ADAR1p110,其中ADAR1p150的表現會受到干擾素的訊號路徑刺激而增加,此外許多文獻指出病毒的RNA也會受到ADAR1的修飾。因此ADAR1被認為參與在干擾素的相關路徑當中,但是目前對於ADAR1在其中扮演的角色仍舊不是很清楚。在本篇研究中,我們利用siRNA抑制ADAR1的表現,證實IFI27L1、 IFNAR1、 IFNAR2、 MAVS、 RIG-1皆受到ADAR1的修飾,其中IFI27L1的mRNA有增加的趨勢。另一方面,PRKRA的mRNA和蛋白質表現量有明顯的下降,而根據次世代定序資料庫的資訊,我們證實在PRKRA轉錄本的下游有一段與之重疊的反義轉錄本,同時此反義轉錄本也會受到ADAR1的修飾。我們發現當ADAR1的表現被抑制後,此反義轉錄本的表現量以及RNA半生期都有增加的趨勢。綜合上述結果,我們發現許多參與在RLR以及JAK/STAT訊號路徑的基因,都會受到ADAR1的修飾;此外我們推測ADAR1能藉由與反義轉錄本的相互作用,進而影響到相關基因的表現。 | zh_TW |
dc.description.abstract | ADAR1 enzyme catalyzes deamination of adenine(A) on double stranded RNA to yield inosine(I). Because inosine is recognized as guanine by cellular machineries, such ADAR1-meidated post-transcriptional nucleotide sequence modification can affect several gene expressions and biological processes. Several studies have demonstrated that, in addition to cellular targets, viral transcripts are substrates for ADAR1, and that ADAR1 exhibits both anti-viral and proviral activities. Interferon (IFN), acting as an antiviral agent, is known to induce the expression of ADAR1 p150 isoform, further suggesting that ADAR1 may be linked to the IFN signaling pathway; however, its roles in this regulation remains uncharacterized. Our recent deep sequencing approach of identifying gene targets of ADAR1 revealed several candidate genes with functions associated with RLR and JAK/STAT signaling. We tested and confirmed editing events and RNA expression level of IFI27L1, IFNAR1, IFNAR2, MAVS, RIG-1 and PRKRA. The A-to-I editing events are confirmed by Sanger sequencing, which further showed obvious ADAR1-dependent editing events in IFI27L1, IFNAR1, IFNAR2, MAVS and RIG-1. Furthermore, higher RNA expression level of IFI27L1 is detected in ADAR1 knockdown cells. With regard to the PRKRA transcript, our observation and sequencing data further imply that there is an anti-sense transcript overlapping with 3’ end of the PRKRA gene locus and that RNA editing may be linked to its regulation. Intriguingly, both mRNA as well as protein expression are decreased and half-life time of the antisense transcript is increased after ADAR1 knockdown. Based on these preliminary findings, we hypothesize that ADAR1 may affect these genes at post-transcriptional level, and in turn modulate the associated signaling pathway. Future work focused on dissecting the mechanism of ADAR1 function in RLR and JAK/STAT signaling as well as in the regulation of PRKRA expression is discussed. | en |
dc.description.provenance | Made available in DSpace on 2021-05-17T09:15:28Z (GMT). No. of bitstreams: 1 ntu-101-R99448016-1.pdf: 3368853 bytes, checksum: 0a5876de8faa722c81bb3653df7c8e8f (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 致謝 I
CONTENTS II 摘要 IV ABSTRACT V 1. INTRODUCTION 1 1.1 Adenosine deaminases acting on RNA (ADARs) family 1 1.2 Retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway 2 1.3 Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway 4 1.4 Protein kinase, interferon-inducible double stranded RNA-dependent activator (PRKRA) 5 2. MATERIALS AND METHODS 7 2.1 Cell culture 7 2.1.1 Interferon-gamma treatment 8 2.1.2 Polyinosinic: polycytidylic acid (poly(I:C)) treatment 8 2.1.3 Actinomycin D treatment. 9 2.2 siRNA transfection 9 2.3 RNA extract and reverse transcription 10 2.4 Primer design for end-point polymerase chain reactions and quantification real time polymerase chain reactions 11 2.5 End-point polymerase chain reactions 12 2.6 Quantification real time polymerase chain reactions 12 2.7 Preparation of cell extract 13 2.8 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) 13 2.9 Preparation of polyacrylamide gel 15 2.10 Rapid amplification of 3’ complementary DNA ends (3’ RACE) 16 2.11 Preparation of DNA constructs 16 2.12 Preparation of agar plate and plasmid transformation 17 3. RESULTS 18 3.1 Editing sites of genes involved in RLR and JAK/STAT signaling pathway predicted in our NGS data were confirmed by Sanger sequencing. 18 3.2 Expression level of mRNA and edited fragment of most target genes were not altered after ADAR1 knockdown. 19 3.3 RNA stability of IFNAR1 IFNAR2 and IFI27L1 was not changed after ADAR1 knockdown. 20 3.4 mRNA and protein expression level of PRKRA was reduced after ADAR1 knockdown. 21 3.5 A predicted antisense was overlapped with 3' UTR of PRKRA by combining the bioinformation from University of California Santa Cruz (UCSC) and Generic Genome Browser (GBrowser) database. 22 3.6 The existence and rough location of the antisense transcript was investigated by 3’ RACE. 23 3.7 RNA stability of the antisense transcript was improved after ADAR1 knockdown. 25 3.8 PKR phosphorylation would be reduced after ADAR1 knockdown under stress condition. 25 3.9 mRNA expression of IFNB1, PKR and STAT1 induced by poly(I:C) was not altered after ADAR1 knockdown. 26 3.10 Antisense transcript was up-regulated after poly(I:C) treatment. 27 4. DISCUSSION 28 4.1 Numerous genes involved in immune signaling pathways were edited by ADAR1. 28 4.2 PRKRA may be regulated by the antisense transcript which were edited by ADAR1. 29 4.3 ADAR1 was associated with virus infection. 31 4.4 Our NGS data provides various target genes which were worth to study. 32 5. REFERENCES 34 6. FIGURES 39 7. TABLES 74 | |
dc.language.iso | en | |
dc.title | ADAR1於干擾素訊號路徑中角色的研究與探討 | zh_TW |
dc.title | Roles of ADAR1 in IFN-signaling pathway | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 譚賢明 | |
dc.contributor.oralexamcommittee | 徐立中 | |
dc.subject.keyword | 雙鏈RNA特異性腺苷,脫氨酶,RNA 編輯,反義轉錄本,干擾素訊號路徑, | zh_TW |
dc.subject.keyword | ADAR1,RNA editing,antisense transcript,IFN-signaling pathway, | en |
dc.relation.page | 77 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2012-08-09 | |
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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