臺灣博碩士論文加值系統

RNA編輯作用廣泛存在於人類轉譯體中，而當RNA被編輯後，會影響目標基因後續功能之改變。在人類細胞中進行RNA編輯主要藉由ADARs家族作用，其共有三個成員：ADAR1、ADAR2和ADAR3；其中ADAR1及ADAR2可將雙股RNA上的腺苷酸去胺基變為肌苷酸。因其結構類似於鳥苷酸，後續功能將其當成鳥苷酸使用，這樣的改變造成後轉錄調控使許多生物功能性轉變。實驗室從NGS資料中得到兩基因為RNA編輯對象：病毒感染相關之基因（PACT）之對股反意義股及Unc80；其分別為ADAR1和ADAR2編輯對象。首先我們驗證出ADAR1透過後轉錄調控ASPACT，並且調控目標基因PACT表現。宿主免疫反應是對抗外來病原的第一線，透過宿主病毒RNA辨認接受器是起始有效率的反病毒免疫作用原點，而這樣的保護機制需要病毒感應器及調控因子—PACT。我們在此論文報導一新穎PACT基因之對股非編碼RNA；透過公開基因資料庫我們得知此新穎非編碼RNA與PACT是3端重疊且高度表現在病毒感染情形下經由STAT-1/2路徑。進一步實驗驗證ASPACT同時抑制PACT之表現量及轉錄本位置；在轉錄層面中，ASPACT佔據PACT染色質且吸引組蛋白沉默子（HDAC1）過來執行功能。同時ASPACT也被發現透過RNA–RNA交互作用具有操控PACT之nuclear retention功能。綜合以上實驗我們確認非編碼轉錄本ASPACT可透過轉錄前及轉錄後抑制PACT之功能，且掀開一宿主免疫反應之新穎調節器。
除了非編碼RNA外，Unc80編碼序列上有ADAR2所調控之RNA編輯位（A8194G），並將其第2732號胺基酸則由絲胺酸改變成為苷胺酸。Unc80為Nalcn離子通道之重要鷹架蛋白，並透過調控細胞膜外鈉離子及鉀離子濃度影響神經刺激性（excitability）。為確認Unc80 RNA編輯事件所造成之生理影響，實驗室利用CRISPR/Cas9系統建立Unc80基因轉殖鼠，其小鼠模擬Unc80之RNA編輯前(Unc80A/A)及編輯後(Unc80G/G)，Unc80A/G為控制組。初步結果顯示，小鼠嗅球及小腦腦區域皆有高程度編輯現象，我們利用動物行為模式評估小鼠嗅覺及動作協調性。行為實驗結果顯示，編輯後(Unc80G/G)小鼠比編輯前(Unc80A/A)小鼠嗅覺差，但Unc80編輯前(Unc80A/A)小鼠平衡能力較正常小鼠差。這說明了Unc80 RNA編輯事件於嗅球及小腦腦區域是具有意義的，根據研究結果指出，Unc80會受到ADAR2的編輯，其編輯事件的發生可能會影響Unc80及其相互作用蛋白的結合力，進一步影響鈣離子流動，而導致神經細胞膜電位改變，最終影響小鼠嗅覺及平衡功能。這也為我們在RNA編輯中揭開了新的面紗。

Adenosine deaminase acting on RNA-1/2 (ADAR1/2) enzymatically mediate RNA editing by converting adenosine into inosine on double-stranded RNAs. As inosine is considered as guanosine, such recoding event leads to post-transcriptional nucleotide sequence modification that can affect many genes expression and biological processes. According to our deep sequencing data on RNA editome, two genes – antisense noncoding RNA of interferon-inducible protein kinase RNA activator (PACT), ASPACT, and Unc80 – are editing targets of ADAR1 and ADAR2, respectively. We first outlined the roles of ADAR1 in the post-transcriptional regulation of ASPACT and focused on the link of ASPACT in the regulation of PACT. The innate immune system is the frontline host protection against pathogens. This protective response requires another viral sensor and immunity factor, PACT. We reported the identification and characterization of a novel antisense PACT gene that expresses a noncoding RNA in a convergent and interferon-inducible manner. Publicly available gene structure and expression data revealed that this gene, overlaps with the 3′-end of the PACT locus and is highly expressed during viral infection, which is dependent on STAT-1/2. We discovered that downregulation of ASPACT impacts both the expression and localization of the PACT transcript. At the transcription level the ASPACT RNA occupies distinct chromatin regions of PACT gene and is important for promoter recruitment of the epigenetic silencer, HDAC1. In parallel, ASPACT was also found to mediate nuclear retention of the PACT mRNA via direct RNA–RNA interaction. In summary, our results support that ASPACT acts as a negative regulator of PACT at multiple levels, and reveal a novel regulator of the viral counteractive response.
In addition to noncoding RNA, a coding site in the Unc80 transcript was revealed by our RNA-seq data. A recoding site of A-to-I editing (A8194G) in the Unc80 showed amino acid change from serine to glycine. Unc80 is a key adaptor component of NALCN ion channel complex that influences neuronal excitability through the extracellular Na+/Ca2+ ion concentration. Sanger sequencing on wild-type and Adar2 knockout mouse brain tissues confirmed that the ADAR2 enzyme is responsive to the neuronal A-to-I editing. To functional interrogate this sequence alteration on UNC80 protein, we generated the Unc80 knock-in mice – corresponding to gain-of-editing and loss-of-editing alteration (Unc80A/A and Unc80G/G, respectively) – using the CRISPR/Cas9 gene targeting technology. Owing to the brain-enriched and regional variable expression of Unc80 and its editing degree, we performed relevant behavioral assessment on animal models to test the effects of different gene product on the olfaction and motor balance phenotypes. Behavioral studies demonstrated that Unc80G/G mouse has impaired olfaction and Unc80A/A mouse has deteriorated balance ability. Taken together, these results suggested that RNA editing on Unc80 might alter particular neuronal functions by affecting calcium influx and binding affinity towards partner proteins. This research will help us further understand the biological significance and the neuronal relevance of a novel RNA editing event.

Table of Contents
Recommendation Letter from the Thesis Advisor ...
Dissertation Oral Defense Committee Certification.
Acknowledgments iii
Chinese Abstract iv
English Abstract vii
Table of Contents x
List of Figures xii
List of Tables xiv
Chapter 1 Background and Introduction 1
Section 1.1 Adenosine deaminase that acting on RNAs (ADARs) family 1
Section 1.2 Long noncoding RNAs 3
Section 1.3 Interferon-inducible protein kinase RNA activator (PRKRA / PACT) 5
Section 1.4 Unc80, Nalcn channel complex subunit (c2orf21 / KIAA1843) 7
Chapter 2 Materials and Methods 9
Chapter 3 Results 22
Section 3.1 A novel antisense RNA ASPACT confers multi-level suppression of PACT and associated signaling 22
Section 3.2 The role of RNA editing in the regulation of ion channel complex scaffold protein, Unc80 37
Chapter 4 Discussion 42
References 51
Figures 62
Table 100



List of Figures
Figure 1. The editing sites of PACT were labeled in UCSC database..... 62
Figure 2. The A-to-I editing events were confirmed by Sanger sequencing
and RNA immuno-precipitation assay .... 63
Figure 3. The A-to-I editing events were confirmed by Sanger sequencing
and RNA immuno-precipitation assay .... 65
Figure 4. The expression of the ASPACT transcript unit ... 67
Figure 5. The nascent RNA of ASPACT is edited by ADAR1 . 70
Figure 6. RNA expression level of ASPACT is regulated by RNA editing.
... 71
Figure 7. Expression level of PACT is affected by ADAR1 ...... 73
Figure 8. Regulatory role of ASPACT in PACT expression 75
Figure 9. ASPACT negatively regulates PACT expression at the
transcriptional level ..... 77
Figure 10. ASPACT associates with HDAC1 and mediates its promoter
recruitment ..... 80
Figure 11. ASPACT mediates nuclear retention of PACT mRNA via
direct RNA–RNA interaction .... 82
Figure 12. Regulation at the post-transcriptional level has a greater impact
on the abundance of PACT protein .. 84
Figure 13. Functional link of ASPACT to the innate immunity 85
Figure 14. Functional link of ASPACT to the innate immunity 87
Figure 15. ASPACT overexpression does not affect the translational rate
of PACT mRNA ... 89
Figure 16. Schematic models of RNA editing in the regulation of
ASPACT and multi-level suppression of ASPACT on PACT ... 90
Figure 17. The confirmation of editing site on Unc80 . 92
Figure 18. The genes of Nalcn channel complex are not affected by
Unc80 overexpression . 93
Figure 19. The calcium influx was altered by RNA editing in N2a cells ....
... 94
Figure 20. The habituation and dishabituation test of Unc80 knock-in
mice .. 95
Figure 21. The RNA and protein expression levels in olfactory bulb of
Unc80 knock-in mice in response to isoamyl acetate treatment 96
Figure 22. The ladder walking test of Unc80 knock-in mice ..... 97
Figure 23. The rotarod performance test of Unc80 knock-in mice ... 98
Figure 24. The triple horizontal bars test of Unc80 knock-in mice .. 99

List of Tables
Table 1. Primer sequence .. 100

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