Dr. Tarn, Woan-Yuh 譚婉玉 博士
Ph.D. National Tsing Hua University
Postdoc Assoc. Yale University
Post-transcriptional regulation in neuronal and cancer cells
My laboratory focuses on mRNA splicing and translation control in neuron and cancer, as well as the cellular function of lncRNAs. Alternative splicing provides a means for development- and tissue-specific gene expression. We investigate how alternative splicing programs neuronal cell differentiation and impacts brain development. The RNA binding protein RBM4 plays a role in neuronal cell differentiation and radial glial migration via alternative splicing regulation. Rbm4 knockout impaired neurotrophic signaling and hence affected cerebellar foliation. Prenatal supplementation of neurotrophin receptor agonist can rescue cerebellar development of newborn mice (submitted). RBM4 indeed regulates alternative splicing of the upstream regulators of neurotrophic signaling. In our second project, we study how RNA helicase DDX3-mediated translational control influences cancer progression. We recently reported that DDX3 promotes the translation of secretory oncogenic factors via its association with the signal recognition particle on the ER. Cancer-derived mutants of DDX3 exert higher potential to translate those pro-tumorigenic factors and hence contribute to the pro-tumorigenic microenvironment. More recently, we found that DDX3 regulates tumor immune surveillance. Therefore, inhibition of DDX3 may be an adjuvant therapy for anti-cancer treatment. In our third project, we study the role of an lncRNA in DNA double strand break (DSB) repair. We identified an lncRNA ribonucleoprotein complex containing both RNA processing and DNA repair factors. This lncRNA recruits specific ribonucleases to degrade DSB induced transcripts at DNA lesions (revised). Finally, we found that this lncRNA can co-phase separate with a RNA processing factor to form liquid-like droplets, suggesting DNA repair condensates at damage sites (revised). We would continue to unveil the importance of RNA regulation.
轉錄後調控對癌症及腦發育之影響
本人實驗室研究癌症和神經元中的 mRNA 剪接和轉譯調控，以及 lncRNA 的細胞功能。選擇剪接是調節發育和組織特異性基因表達的一種方法，RNA結合蛋白RBM4 通過剪接調控影響神經元細胞的分化和遷移，Rbm4 剔除造成小鼠之神經營養蛋白信號傳導受損，而出現小腦葉狀結構異常之現象。近一步研究則發現， RBM4 通過選擇性剪接可控制神經營養因子調節劑的表達，並與神經細胞的其他剪接調節分子協同發揮作用。我們的第二項計畫是研究RNA 解旋酶 DDX3 如何利用轉譯控制影響癌症進展，我們最近報導DDX3 經由內質網上的mRNA 轉譯產生分泌性致癌因子，進而影響腫瘤微環境和血管新生，DDX3 的突變具有更高的能力可促進這些腫瘤因子的產生，此外我們發現 DDX3 利用一種新的機制調節腫瘤免疫監視的功能，因此抑制 DDX3 可能是抗癌治療的輔助療法。我們的第三個項目旨在了解非編碼RNA (lncRNA) 的分子和細胞功能。我們最近發現了一種 lncRNA，它和RNA 加工分子和 DNA 修復分子結合成大型核醣核蛋白複合物，並參與 DNA 雙股鏈斷裂修復。這種 lncRNA 會募集核醣核酸酶來降解DNA損傷位點附近的RNA，從而加速 Ku70/80 的置換。此外，我們還研究 lncRNA 是否在 DNA損傷處與 DNA 修復因子形成液體狀凝聚物的可能性。結果顯示RNA 加工分子 Y14 確實與該 lncRNA 共相分離形成液滴，這種能力對於細胞中的 DNA修復非常重要。我們將繼續研究 RNA 調控如何參與細胞反應，以及當其功能失調後如何導致發育缺陷和疾病。
