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標題: | 全面性分析在自閉症表現量異常的環狀核糖核酸及環狀核糖核酸–微小核糖核酸–信使核糖核酸間相互調控網路 Integrative analysis of circular RNA dysregulation and circular RNA-microRNA-mRNA regulatory axes in autism |
作者: | Yen-Ju Chen 陳彥如 |
指導教授: | 莊樹諄(Trees-Juen Chuang) |
關鍵字: | 自閉症,環狀核糖核酸,微小核糖核酸,基因調控網路, Autism spectrum disorder,ASD,circular RNA,circRNA-microRNA-mRNA,circARID1A,has-miR-204-3p, |
出版年 : | 2020 |
學位: | 博士 |
摘要: | 自閉症譜系障礙是一種腦部發展障礙所導致的複雜疾病,患者特徵有社交溝通與互動障礙,侷限且重複的行為或興趣,有些伴隨不同程度語言發展障礙。在已開發國家中約有1-2% 孩童被診斷罹患自閉症。普遍認為自閉症與遺傳因素有相當大的關係,然而患者間在基因變異上有很大的差異,因此目前對自閉症的致病機轉仍不甚了解。許多研究發現自閉症與特定的基因變異有關,其所影響的功能多和神經元活性及可塑性、突觸連結以及免疫和發炎反應等相關。而在核糖核酸1層次上,後轉錄調控機制是否參與在自閉症致病機轉仍不甚了解,尚待進一步探討。
藉由人腦組織的轉錄體與表觀基因體分析發現,許多自閉症患者上表現異常的生物標記,如信使RNA (mRNA)、 微小RNA (miRNA) 、長非編碼RNA (lncRNA)、多樣性切割以及各種表觀遺傳因子等。近年來陸續有研究指出,環狀RNA(circRNA)與許多神經疾病的發生與神經發育有關,因此具有重要研究價值。環狀RNA是一種非線性RNA,經由先導mRNA反式剪接而成,具有共價閉合的單鏈環狀結構。circRNA能扮演一種miRNA海綿效應,結合互補的miRNA,使其無法抑制下游基因轉錄,而這樣的機轉也被報導在許多神經疾病中,但circRNA是否參與在自閉症調控機轉中目前尚未被探討。 本篇研究中,我們整合上百筆人腦組織的轉錄體定序數據,揭開自閉症患者和非自閉症大腦中circRNA的表現圖譜,發現自閉症患者大腦皮質中存在六十個表現量異常的環狀RNA以及三群共同表達的circRNA。經由整合mRNA、miRNA和circRNA表現量資料,以及預測miRNA結合為結合位,建立出自閉症相關的circRNA–miRNA–基因調控網路。最後我們證實一個在自閉症患者腦部表現量明顯上升的環狀RNA(circARID1A),它能吸附 miR-204-3p進而影響多個自閉症相關基因的表達。這顯示自閉症除了受到風險基因突變影響外,也可能藉circRNA調控miRNA,進而影響下游基因表達。而circRNA–miRNA–基因調控網路的預測方法,未來也可應用在其他複雜神經疾病中,為複雜疾病診斷、追蹤及治療提供新的思考方向。 Autism spectrum disorders (ASDs) are a heterogeneous group of complex neurodevelopmental disorders characterized by impairment in social, communication, and restricted or repetitive behaviors. Despite remarkable genetic heterogeneity, ASD-associated genes have been suggested to target a few convergent biological processes, including synaptic transmission and plasticity, neural activity, and metabolism-related. However, the role of post-transcriptional mechanisms in ASD is largely uncharacterized. In recent years, through analysis of transcriptome and epitranscriptome of human brain tissues, many biomarkers such as messenger RNA (mRNA), microRNA (miRNA), long non-coding RNA, alternatively spliced transcript and various epigenetic factors have been found in ASD patients. Several studies have suggested that circRNAs are involved in the occurrence and development of neurological diseases. Currently, much less is known about the contribution of circRNA in regulatory mechanisms of ASD. Circular RNA (circRNA) is a type of endogenous non-co-linear RNA, which are covalently closed single-stranded RNA molecules derived from the backsplicing of pre-mRNAs. CircRNAs play a regulatory role as miRNA sponges to suppress the downstream targets of complementary miRNAs. In this study, we performed genome-wide circRNAs expression profiling in post-mortem brains from ASD and non-ASD samples. Our analysis revealed 60 differential expressed circRNAs and three perturbed co-regulated modules in ASD. We explored ASD-associated circRNA–miRNA–mRNA interactions, in which target genes were particularly enriched for ASD risk genes and genes encoding inhibitory postsynaptic density proteins. Furthermore, we confirmed that some ASD risk genes were indeed regulated by circARID1A via sponging miR-204-3p in human neuronal cells. Our genome-wide analysis provides a deeper insight into the role of dysregulated circRNAs, as well as the corresponding circRNA–miRNA–mRNA axes in ASD pathophysiology. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7138 |
DOI: | 10.6342/NTU202000765 |
全文授權: | 同意授權(全球公開) |
顯示於系所單位: | 基因體與系統生物學學位學程 |
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