2019-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/652510摘要：智能發育障礙的病人中常出現基因調控失常與DNA甲基化的異常的現象，如ATRX基因突變導致的ATRX syndrome便為一個例子，在ATRX syndrome病人的細胞中會發現在DNA高度的複製序列 （如rDNA，Y-specic satellite and subtelomeric repeats）上有甲基化的異常。利用次世代定序的分析研究結果發現人類ATRX的變異與智能障礙有顯著相關性，推論ATRX基因突變導致表觀遺傳上的變化對於智能發育障礙扮演重要的角色。我們在之前的研究中發現非編碼TERRA RNA (含有telomeric-repeat 的RNA) 與ATRX在調控基因表現上有拮抗作用，TERRA RNA是從染色體端粒（telomeres)中轉錄出來，位於TERRA與ATRX共同結合的基因上，TERRARNA會活化基因表現，ATRX卻是抑制基因表現。這樣的研究結果使我們推測抑制TERRA RNA 可以減緩ATRX基因突變導致表觀遺傳上的變化，進而能治療其智能障礙。我們長遠的計劃是要發展出治療智能障礙的藥物。此計劃的目的著重於研究TERRA RNA如何調控基因表現與測試抑制TERRA RNA的表現是否能減緩ATRX基因突變導致的缺失。此計劃的中心假說是TERRA RNA可與ATRX 拮抗並與histone methyltransferases 結合來調控基因表現。此計劃的目標有三個：第一:測試TERRA RNA是否與將抑制ATRX與基因體的結合來調控整個基因體的基因表現; 第二:測試TERRA RNA是否與histone methyltransferases 結合來調控基因表現; 第三:測試抑制TERRA RNA是否能用來作為對抗 ATRX基因突變所引起的缺失的治療方法。此計劃是具有重要性的，因為能解決TERRA RNA是如何來調控基因表現的問題，並且也能對於治療ATRX syndrome或給予智能發育障礙的病人提供ㄧ個新契機。此計劃所設立的研究是具備創新力，因為染色體端粒變化與調控基因的交互作用還不清楚，推測TERRA RNA可能扮演一個傳遞訊號與溝通的角色，此計劃將深入了解此問題，研究此問題將有助於回答基礎生物的運行機制並對於治療人類疾病有所貢獻。<br> Abstract: Dysregulation of gene expression and altered DNA methylation patterns are usually observed in patients with mental retardation. Patients with ATRX syndrome caused by ATRX mutations showed a dramatical alteration on methylation patterns of several highly repeated sequences, including rDNA arrays, a Y-specific satellite, and subtelomeric repeats (Gibbons et al., 2000). Using targeted next-generation sequencing, ATRX, a chromatin modifier, was reported as one of most common causes of intellectual disability (Grozeva et al., 2015). Thus, epigenetic changes caused by ATRX mutations may play an important role in the pathogenesis of mental retardation. Previously we have shown that telomeric repeat-containing RNA (TERRA) antagonizes ATRX in gene regulation. TERRA is a long noncoding RNA transcribed from subtelomeric regions. We found that TERRA activates while ATRX represses gene expression at their share target sites. This suggests that inhibition of TERRA may alleviate the alteration of gene expression caused by ATRX mutations. Our long-term goal seeks to develop new strategies for the treatment of mental retardation caused by dysregulation of gene expression. The objective of this proposal is to dissect the mechanisms by which TERRA regulates the gene expression and to look for its potential applications for the alleviation of pathogenesis caused by ATRX mutations. The central hypothesis is that TERRA regulates gene expression via antagonizing ATRX and interacting with histone methyltransferases (HMTs). In this project, we will test the following hypotheses: TERRA expels ATRX from chromatin to regulate gene expression throughout the genome (Aim 1). TERRA interacts with HMTs to regulate the gene expression (Aim 2). Depletion of TERRA can alleviate the pathogenesis caused by ATRX mutations (Aim 3). This contribution is significant since it will understand the mechanisms of gene regulation by TERRA, and that will stimulate the development of new therapeutic approaches for ATRX syndrome or other mental retardations. The proposed research is innovative because the communication between telomere dynamics and gene regulation is poorly understood, and our proposed approaches will discover the role of TERRA in epigenetic regulation and the pathway for sending signals between telomeres and outside of telomeres. Insight into the regulation of gene expression by TERRA is impactful on knowledge of fundamental biology and may contribute to the treatments for human diseases.表觀遺傳學 智能發育障礙 甲基化 非編碼RNA 染色體端粒 甲基化&#37238EPIGENETIC methylation MENTAL RETARDATION histone methyltransferases non-coding RNA TERRA ATRX telomere