Ph.D. National Tsing Hua University
Postdoc Assoc. Yale University
Post-transcriptional regulation in neuronal and cancer cells
Post-transcriptional control is important for eukaryotic gene expression and cellular function. We aim to have a comprehensive understanding of the mechanisms of mRNA metabolism and its impact on cell function, for which we focused on alternative splicing and translational control. Alternative splicing greatly increases the complexity of eukaryotic genomes, and provides a means for development- and tissue-specific gene expression. Dysregulation of alternative splicing may cause diseases. We particularly study how alternative splicing programs cell differentiation. We have previously reported that the splicing factor RBM4 is involved in differentiation of muscle and pancreas cells via its role in alternative splicing regulation. More recently, we show that RBM4-mediated splicing regulation also impacts neuronal differentiation and migration during cortical development. In addition we study the post-splicing exon-junction complex that associates with the spliced mRNA and functions in mRNA surveillance. We recently found that one of its components (Y14) plays roles in splicing regulation, mRNA cap binding, and possibly protein stability control. Y14 regulates alternative splicing of p53 and modulates cell sensitivity to genotoxic agents. Our study for the first time establishes a direct link between Y14 and p53 expression and suggests a function for Y14 in DNA damage signaling. We also study the RNA helicase DDX3 in translational control in cancer and neuron. DDX3 promotes the translation of mRNAs containing a complex 5’ UTR, and its target mRNAs encode oncogenic and migration related factors. Therefore, DDX3 contributes to cell cycle control and cell migration in cancer cells. Moreover, DDX3 functions in localized translation in neuron and whereby it modulates neurite and dendrite outgrowth and spin maturation. Our studies provide the details for a wide range of RNA processing events and their regulation mechanisms.
轉錄後調控對於真核細胞的轉錄體 (transcriptome) 表達有相當重要的影響。本實驗室一直在研究mRNA的代謝調控與細胞生理、分化和致病機轉的關係，我們近年在選擇性剪接及轉譯調控方面有具體的成果。 選擇性剪接會大幅增加真核細胞轉錄體的複雜性，並可產生特定發育期和具組織專一性的mRNA isoforms，基因多型性或突變及剪接調控分子失控都可能改變剪接isoform表達的平衡，而使細胞失去正常功能。我們長期研究剪接調控分子RBM4參與的剪接反應和其生物功能，發現RBM4會影響發育基因的isoform表達，因而促進肌肉、胰島及神經細胞的分化，我們最近利用基因剔除小鼠進一步研究剪接調控對大腦皮質發育的影響。我們亦研究剪接後exon junction複合體蛋白Y14的功能，我們發現Y14可參與mRNA剪接甚至影響蛋白的穩定性，我們最近的報導指出Y14會調控p53 isoform的表達及影響細胞對DNA損傷修復的能力。由於RNA解螺旋酶DDX3的突變會引發癌症及神經失能，我們亦同時研究 DDX3的生化及細胞功能，我們發現DDX3會幫助有複雜結構的mRNA進行轉譯，並藉此影響細胞週期和移動以及神經突觸的形成。我們抑制小鼠體內DDX3的表達可順利降低腫瘤形成及癌轉移。我們未來的研究重點仍是要深入瞭解這些mRNA調控的生理意義以及和疾病的關係。