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再生醫學的新希望:表觀基因體之技術突破與應用

 

    高齡化世代來臨,再生醫學在世界各地迅速發展,成為極為重要的研發議題。台大生物科技研究所教授林劭品率領團隊以雞、豬、小鼠與人類之生殖細胞與幹細胞為材料,研究細胞分化與複製動物再程序化過程中,影響基因表現與細胞命運決定之表觀基因體(Epigenomics)調控機制,在學術、技術層面皆大有突破,更提供再生醫學新契機。

    林劭品表示,表觀基因體連接著細胞基因的組成與環境之交互作用,可在不改變DNA序列的情況下,影響各基因是否表現及所表現之劑量,進而決定細胞和個體的命運。即使具有完全相同基因型模式之動植物、家禽畜、作物以及人類同卵雙生之雙胞胎,也會因為光照、氣候或營養等條件不同,產生不同表現型。表觀遺傳學(Epigenetics)因此被喻為後基因體時代最重要之學門,且為發育生物學、轉譯農學與轉譯醫學之重要基礎。由於調節基因表現之表觀基因體修飾標記具有可逆性,因此成為因應氣候變遷對於多年生林木、作物之影響,以及改善伴侶動物、人類健康與再生醫學之希望。

    林劭品說明,由於添加或移除表觀基因體修飾標記之酵素基本上存在於每個細胞內,關鍵問題在於因應微環境之變化,如何(how)由特定分子(what)於特定時機(when)帶領此等酵素至特定基因區位(where)添加或移除特定標記(which marks),以完成細胞功能。因此團隊進行研究與實驗,擁有以下重要貢獻:
(一)解析表觀基因體調節蛋白(如不具酵素功能的類3號DNA甲基化酶)、長短鏈功能性非編碼RNA(non-coding RNAs)引導表觀基因體修飾,調控分化與發育相關基因,及內外源反轉錄病毒與跳躍基因/轉座子(Transposable Element)表現之新穎機制與作用途徑(The What, How, When and Which Marks; 與中研院陳俊安老師、交大洪瑞鴻老師,及臺、美、法合作研究:Nature, 2007,134:417-26; J. Virology, 2014, 88:10680-95; eLife, 2018, 7:e38080; BMC Genomics, 2018, 19:425)。
(二)闡述與驗證生殖幹細胞休眠之多層次分子機制,了解男/雄性動物長期生殖能力維護之基礎,並揭示此一層次之不孕病因,且為季節性生殖之禽畜育種提供新方向(與中研院蕭百忍老師、臺大醫院何弘能院長、北醫大黃彥華主任、慈濟大學靖永皓老師及台、日、美合作研究:Development, 2014, 141:2402-13; Reproduction, 2015, 150:R77-91; Bio-Protocol, 2016, 6: iss 24; Stem Cell Investigation, 2018, 5:11)。
(三)解析人類、豬、雞與小鼠胚幹細胞/誘導型多潛能幹細胞(induced pluripotent stem cell, iPS cells)、生殖細胞、骨髓間葉幹細胞於休眠、自我複製、分化等細胞命運決定相關調控之新穎機制,並發現有效篩選胚幹細胞株之分子標記(MEG3 LncRNA表現及IGDMR甲基化),可大舉提昇幹細胞往神經系統分化之效率及臨床試驗預防癌化之安全性(與臺大基因體與蛋白體醫學研究所陳信孚所長、臺大醫院何弘能院長、中研院郭紘志老師、臺大動科系鄭登貴老師、丁詩同主任、吳信志老師、劉逸軒老師、馬偕醫院李勝祥研究員、胡玉銘主任、李國光主任、林明輝主任合作研究:Stem Cell Research & Therapy, 2015, 6:1; Journal of Biological Chemistry. 2012, 287:14389-401; Journal of Animal Science. 2011, 89(11):3460-72; Biology of Reproduction. 2011, 84:514-25; PLoS One. 2017;12, e0184111; BMC Genomics. 2018; 19:425)。
(四)與臺大生技所宋麗英老師及臺、法、美之多邊合作研究,以與桃莉羊相同之複製動物技術(somatic cell nuclear transfer)研究表觀基因體之可逆性,發現體細胞中H3K9me3抑制型表觀修飾為複製動物成功率低之重要原因之一,並建立受精卵發育早期內源性反轉錄病毒表現與胚胎發育成功率相關性之連結(Reproduction, 2015, 150:245-56)。
(五)此外,於雞隻皮膚分化計劃執行過程,建立並優化由新鮮組織分離之少量細胞為起始樣品,進行染色質免疫沈澱-DNA定序(Chromatin -Immunoprecipitation-Sequencing)之方法學,並成功應用到校內多個研究室(與美國南加大鍾正明院士、臺大動科系林恩仲老師、臺大資工系歐陽彥正老師、臺大生機系陳倩瑜老師合作:BMC Genomics. 2015, 16:22)。
(六)且與臺大生機系盧彥文教授共同研發Lab-on-a-chip平台應用在DNA甲基化分析(Lab on a Chip.18:514-521),提供農業及生醫領域現場應用之優勢。

 

(林劭品老師團隊對於相關領域之介紹及洞見,以『表觀基因體學於再生醫學之貢獻與應用』為題,發表於科技部2018出版之『再生醫學:臨床與產業運用』專書第一章,網址如下:http://homepage.ntu.edu.tw/~scoffice/。)

 

圖一:幹細胞分化與體細胞去分化(再程序化)過程中表觀基因體變化情形。

Technology Breakthrough and Application of Epigenome: A New Hope for Regenerative Medicine

Professor Shau-Ping Lin at the Institute of Biotechnology led a team using chicken, pig, mouse, and human germ cells and stem cells as materials to study the epigenetic body that affects gene expression and cell fate determination (epigenomics) during the process of cell differentiation and replication. The proposed regulation mechanism has made great breakthroughs in academic and technical aspects, and it also provided new opportunities for regenerative medicine. Professor Lin said that the epigenome was connected to the interaction between the composition of cell genes and the environment, which can affect the performance and dosage of each gene without changing the DNA sequence, thereby determining the fate of cells and individuals. Even twins of animals, plants, poultry and livestock, crops, and human identical twins with exactly the same genotype pattern will have different phenotypes due to different conditions, such as light, climate, and nutrition. Epigenetics is therefore hailed as the most important academic field in the post-genome era, and is an important foundation for developmental biology, translational agronomy, and translational medicine. Because of the reversibility of epigenetic modification markers that regulate gene expression, it has become a hope for responding to the impact of climate change on perennial trees and crops, as well as improving companion animals, human health, and regenerative medicine.

The link of the research: http://homepage.ntu.edu.tw/~scoffice/

Figure. Changes in epigenome during stem cell differentiation and somatic cell de-differentiation (reprogramming)

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