Regulation of Signal-Dependent TLR9 Alternative Splicing and Its Impact on Immune Gene Expression in Grouper

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Project title

Code/計畫編號

MOST104-2313-B019-006

Translated Name/計畫中文名

石斑魚Toll-like receptor 9訊息依賴性RNA選擇性裁剪之調控機制及其對於免疫基因表現的影響

Project Coordinator/計畫主持人

Pin-Wen Chiou

Funding Organization/主管機關

National Science and Technology Council

Department/Unit

Department of Aquaculture

Website

https://www.grb.gov.tw/search/planDetail?id=11581087

Year

2015

Start date/計畫起

01-08-2015

Expected Completion/計畫迄

31-07-2016

Bugetid/研究經費

700千元

ResearchField/研究領域

生物技術(農)
漁業

"宿主的類鐸受體（Toll-like receptors)在偵測辨識入侵病原體及調控相對應之免疫反應中扮演關鍵角色。類鐸受體9 (TLR9)能辨識細菌及DNA病毒體基因體上非曱基化的CpG序列，經由下游訊息傳遞產生與炎症或干擾素反應相關的細胞激素。石斑魚（Epinephelus spp)具有兩個亞型的 TLR9(gTLR9A及gTLR9B)。我們先前發現石斑魚的TLR9訊息傳遞系統演化出一套獨特的調控系統： gTLR9B能負調控gTLR9 pathway，且其形成是受到RNA選擇性裁剪的調控；比較不同魚種的亞型TLR9 核酸序列顯示，此機制也可能存在與石斑魚演化親緣性相近的魚種中。我們進一步發現RNA Pol II 速率的改變會影響gTLR9 pre-mRNA裁剪的結果，顯示gTLR9 pre-mRNA的選擇性裁剪是與RNA轉錄機組（transcription machinery)耦合(coupling)。此外，我們的初步實驗也發現TLR9 pathway下游的NF- k B能調控gTLR9 pre-mRNA裁剪而導向gTLR9B mRNA生成。目前對於動物細胞内RNA選擇性裁剪調控TLR訊息傳遞雖已有研究，但是對於TLR訊息傳遞本身對於RNA選擇性裁剪的影響則尚未有深入探討，石斑魚TLR9正可做為此項研究的模式。因此，本計晝擬深入探討石斑魚TLR9訊息依賴性RNA選擇性裁剪關係中的相互調控機制，並進一步分析其對於其他免疫相關基因表現的影響。" "Toll-like receptors play a critical role in the recognition of invading pathogens, which is an essential step to the onset of proper immune response. TLR9 recognizes unmethylated CpG dinucleotide found in the genomes of bacteria and DNA viruses, resulting in the production of inflammatory cytokines and/or interferons. In our previous study, we have identified two isoforms of TLR9, namely TLR9A and TLR9B, in orange-spotted grouper (Epinephelus coioides). TLR9B is a truncated isoform and can negatively regulate the expression of downstream genes such as IL-1P. Grouper (and phylogenetically close species) TLR9 system has developed a unique mechanism not found in the TLR9 pathway of other vertebrates to control TLR9 signaling, in which the production of the negative regulator gTLR9B is mediated by RNA alternative splicing (AS). In subsequent preliminary study, we found that the alteration in the elongation rate of RNA pol II could affect the outcome of gTLR9 pre-mRNA splicing, indicating the alternative splicing event is coupled with the transcription machinery. In addition, NF-kB (a TLR9 downstream molecule) may play a role in the AS-mediated generation of gTLR9B. Although extensive studies have been devoted to the understanding of TLR pathways mediated by RNA AS in mammalian cells, the understanding of how TLR pathways mediate RNA AS has been scarcely addressed in any animal species. In this project, we seek to further characterize the mechanisms of the signal-dependent TLR9 alternative splicing, and its impact on the expression of immune-relevant genes in grouper."

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Regulation of Signal-Dependent TLR9 Alternative Splicing and Its Impact on Immune Gene Expression in Grouper

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