2014-01-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/657605摘要： 父方及母方來源的染色體，在功能上是不同的。此現象是由於染色體上的印記所造成。染色體上的印記，開始於精卵形成的過程中，並終生維持此印記。染色體上的印記，是經由表觀基因的模式來修飾，此修飾進而造成印記基因的表現，受到來自父方或母方染色體來源的調控。染色體上的印記，主要發生在大腦中。然而，我們對染色體上的印記之了解，卻是十分有限的。這是因為染色體上的印記，不但會受到時間及空間上的調控，而且還會受到環境、性別、物種及基因異構體的影響。印記基因在調控上的缺失，將會造成許多與腦相關的人類疾病，例如Autism、Angelman syndrome、Prader-Willi syndrome、Rett syndrome、Turner’s syndrome及myoclonus-dystonia syndrome。由於染色體上的印記對人類疾病之影響，扮演極為重要的角色，因此有著迫切的需要，去找出所有在大腦中的印記基因，以及研究其在大腦內所扮演的角色。由於繁雜的大腦細胞種類及複雜的染色體印記之調控，因而，這是非常重要地去全方位檢測，在大腦中，不同細胞、時間點及外在環境調控的印記基因。最重要的是，我們已開發出一套可檢測出在不同細胞及時間點表現的印記基因之研究平台。在我們最初的檢測中，我們己找出一個全新且具神經元專一性的印記基因。根據此發現，我們假設許多與疾病相關聯的印記基因，可受不同的細胞種類、發育時間點或外在環境來調節。我們將用以下參個策略，來測試我們的假設：策略一:檢測在老鼠腦中不同細胞種類表現的印記基因策略二:偵測在老鼠腦中不同發育及老化時間點表現的印記基因策略三:檢測在老鼠腦中受不同外在環境調控的印記基因完成此構想工作，我們將可提供第一個在不同時間點、各種腦細胞種類及受外在環境調控表達的印記基因圖譜。更重要的是，經由此工作所累積的經驗及知識，將可協助未來在檢測人類腦中，在不同發育及老化時間點和各種腦細胞表達的印記基因。我的實驗室之長遠目標，是在人類及老鼠腦中，建立一個全方位的印記基因圖譜，此圖譜有著不同細胞種類、時間點、外在環境、性別及物種的解析度。在此印記基因圖譜上，我們將可提供染色體印記相關疾病的新治療模式，及加深對大腦演化、功能和疾病的認識。<br> Abstract: Genomic imprinting is an epigenetic process by which certain genes are expressed in a parent-of-origin-specific manner. Genomic imprinting predominantly occurs in the mammalian nervous system. Dysfunctional genomic imprinting causes a variety of neurological and psychiatric disorders, e.g., autistic spectrum disorders, Angelman syndrome, Prader-Willi syndrome, Rett syndrome and Turner syndrome. Despite the importance of genomic imprinting in the human brain, its roles in the brain are still unclear. The key obstacles to advances in the field of genomic imprinting in the brain are the complex expression patterns of imprinted genes and the heterozygous nature of the brain. The expression of imprinted genes can be regulated by different cell types, developmental stages, and the environment. Our brains contain various cells such as pyramidal neurons, interneurons, and glial cells. In addition, maturation of the mammalian brain is developmentally and environmentally regulated. Therefore, these three factors – cell type, developmental stage, and environment – must be considered to address the roles of genomic imprinting in the brain. To comprehensively determine the imprinted genes of the mammalian brain on a whole genome-wide scale, we will use fluorescence-based laser-capture microdissection and RNA-sequencing approaches. Specifically, we will profile imprinted genes in the mouse brain with cellular, temporal, and experience-regulated resolution. Upon finishing this project, we will be uniquely positioned to comprehensively profile parent-of-origin expression in the human brain with cellular and temporal resolution, which is poorly characterized. The long-term goal for my laboratory is to construct a comprehensive genetic map of parent-of-origin-specific expression in the mouse and human brains with cellular, temporal, experience-regulated, gender-, and species-specific resolution. The results from our studies could provide new insights into genomic imprinting in the context of neurological and psychiatric diseases and may deepen understanding of brain evolution, function and diseases.神經表觀遺傳學基因組印記神經發育疾病NeuroepigeneticsGenomic imprintingNeurodevelopmental disorders