DNA甲基化在生物發育的進程中扮演了許多重要角色，過去一直認為在胞嘧啶上進行甲基化(5mC)是個穩定且遺傳自親代的一種表觀遺傳，直到TET雙去氧酶被發現具有氧化5mC成為5-hydromethylcytosine (5hmC)、5-formylcytosine(5fC)及5-carboxylcytosine (5caC)的能力後，才被指出胞嘧啶並非只有在5mC與非甲基化之間轉換。許多研究證明DNA甲基化及去甲基化對於神經發育十分重要，有不少研究推論TETs與神經發育與分化有關，此關聯不在於去甲基化的機制，而是5hmC在神經元細胞中基因表現與否與神經細胞再生扮演很重要的角色。此外，甲基化調控對腦部調節壓力、神經發育、失智行為以及老化有極大的關聯，雖然TETs被認為在其中也扮演了重要角色，但由於TET雙去氧酶的基因缺失在哺乳類動物模型中無法存活，故以小鼠為動物模式的研究有限。本計畫中預計建立斑馬魚tet基因剔除品系，進行行為分析，在計畫結束前利用甲基化基因譜的分析，藉由系統化的研究進行潛在基因網絡的預測與分析，試著了解TETs基因的去甲基化功能基因缺失與認知行為的關連。
DNA methylation plays an important role on epigenetic regulations. TETs, a group of dioxygenases that oxidize 5-methlycytosine (5mC) to 5-hydromethylcytosine (5hmC), 5-formylcytosine(5fC) and 5-carboxylcytosine (5caC), were considered important to neuronal development. Previous studies demonstrated the DNA methylation pattern was associated with environmental-stimulated animal behaviors; however, due to embryonic lethal of tet family-knockout in mice the tissue specific mutagenesis demonstration was insufficient to characterize the network of TETs. Therefore, we first aimed to establish a zebrafish model to unveil the function of tets on modulating fish behaviors. We applied various endpoint examines to evaluate the behavior of the wild type, tet1, tet2 and tet3 knockout zebrafish. In this project, we found that the mutated methylated pattern caused anxiety-induced dementia. With comparison of wild type, tets transgenic model, a whole genomic epigenetic profiling showed methylation network between tet and pallium processing. In addition, NOTCH signaling, which is important to embryonic development, was also associated with TETs network through prediction. Taken together, our project will not only establish a platform to examine dementia behaviors in zebrafish model, but also fully clarify TETs function. We have finalized our research and article composing at this moment. Hopefully we are able to have our finding published and make a big hit in the near future.
