Dr. Huang, Yi-Shuian 黃怡萱 博士
Ph.D. University of Texas Southwestern Medical Center at Dallas
Neurons receive thousands of synaptic connections from others and modify the strength of individual synapses independently with varying degrees of stability. This experience-dependent synaptic plasticity underlies the molecular and cellular basis of learning and memory. Regulated local translation allows for remote control of gene expression to concentrate proteins in subcellular compartments such as synapses and is important for synaptic plasticity and memory. Thus, we study cytoplasmic polyadenylation element binding proteins (CPEBs), which regulate the translation of target mRNAs for memory and other physiological functions.
Several chemical modifications in mRNAs have been identified to regulate posttranscriptional gene expression. However, the mechanisms underlying epitranscriptome-controlled translation remain largely unexplored. Thus, we also investigate the molecular and physiological functions of cap methyltransferases (CMTRs). Eukaryotic mRNAs are 5'-end capped with a 7-methylguanosine (m7GpppNN, N: any nucleotide), which is important for processing, transport, and translation of mRNAs. The cap structure in higher eukaryotes is further methylated at the 2'-O-ribose position of the first and second nucleotides by CMTR1 and CMTR2. The cap1 structure (m7GpppNmN) is generally believed to mask mRNAs from innate immune surveillance. However, we found that CMTR1-catalyzed 2'-O-methylation is important for gene regulation and brain development independent of silencing innate immunity.
記憶如何形成和儲存在我們的腦中，是個有趣卻看似抽象的生物問題。隨著日新月異的技術和基因工程動物的發展，我們逐漸開始了解它的分子機制。在動物的中樞神經系統，神經細胞靠著特有的突觸結觸彼此傳遞訊息。每個突觸是個有塑性的訊息收發個體，會隨著所收到的訊息強度和次數而改變自己的結構，功能及數目，因而加強或減弱特定訊息的迴路。這種突觸可塑性是記憶形成的分子機轉。我們已知若要形成長久性的記憶，需要合成新的蛋白來維持突觸的結構改變。所以這些新合成的蛋白質被認為是組成記憶的分子體。細胞常藉由一群會和核醣核酸結合的蛋白 (RNA-binding proteins) 來選擇性的調控特定RNA的轉譯及蛋白的產生，因此，我們選擇了CPEB家族蛋白。希望藉由瞭解其在神經中的功能，去找出和記憶有關的蛋白分子體。
我們的另一研究重點是探討所知極少的帽甲基轉移酶的生理功能。近期的研究發現，轉錄後的基因調控，不僅取決於訊息核醣核酸 (mRNA) 的序列，還取決其核糖和鹼基的化學修飾。在所有真核生物中，mRNA的加帽修飾 (capping)，可保護其免於降解並促進其轉譯。除了酵母菌僅具有原始的m7G帽 (cap0)，其他高級真核生物mRNA的第一和第二核苷酸，可分別被帽甲基轉移酶CMTR1和CMTR2在2'-O-核糖位置甲基化。通常認為cap1結構 (m7GpppNmN) 可以避免引發先天免疫反應。但是，我們發現CMTR1對於腦發育的重要性是透過調控基因表達而非是防止先天免疫反應。
