Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/20321
標題: 複製動物基因體中銘印及/或非銘印基因之甲基化樣貌剖析
Dissecting methylation profiles of imprinted and/or non-imprinted genes in cloned animal genomes
作者: 沈志傑
Shen, Chih-Jie
關鍵字: 去氧核醣核酸甲基化;DNA methylation;上遺傳性修飾;銘印基因;核轉置技術;複製動物;再程式化作用;差異性甲基化區域;甲基化結合區;差異性甲基化雜合作用;染色體免疫共沉澱;衛星基因座;Epigenetic modification;Imprinted genes;Somatic nuclear transfer technique;Cloned animals;Reprogramming process;Differentially methylated regions;Methyl binding domain;Differentially methylated hybridization;Chromatin immunoprecipitaion;Satellite gene locus
出版社: 生命科學系所
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摘要: 
在哺乳類的基因體中,去氧核醣核酸甲基化(DNA methylation)為主要上遺傳性修飾(epigenetic modification)之一,並調控著許多基因的重要功能表現。利用體細胞核轉置技術(somatic cell nuclear transfer technique; SCNT)所產生的哺乳動物常伴隨著妊娠或出生時的發育失敗風險,且其成功產製出活體複製動物的比例亦極為稀少。甚且成長至成體的複製動物也常有許多器官發育或遺傳上的變異,目前研究學者普遍歸咎這些原因可能為不恰當的上遺傳性修飾。單一親緣染色體表現之銘印基因(imprinted genes)是一群調控胚胎正常生長及發育的重要因子,本研究結果顯示在外表看似正常的複製動物基因體中,其銘印基因的預測差異性甲基化片段(putative differentially methylated regions; putative DMRs)仍然存在著許多異常甲基化修飾。吾人發現並鑑定出在豬及牛基因體中銘印基因之預測差異性甲基化片段的甲基化銘印模式在人工性核轉置過程是非常的不穩定;此等混亂的甲基化修飾現象,推測係略過正常精卵受精所需的再程序化作用(reprogramming process)所使然。已分化的體細胞其細胞核並沒有像生殖細胞一樣接受正常的再程序化作用,對一些已知的上遺傳修飾性位點達到正確位置及時間點上的移除,這些不恰當的親緣銘印性修飾資訊將被帶進複製動物的基因體中,因而影響基因的表現且引起非預期的病症。OPN及H19基因的甲基化調控片段是經由甲基親和性結合區(methyl-binding domain; MBD)蛋白所分離出來,這些片段並在複製豬耳朵組織的基因體中呈現異常甲基化的型態,吾人亦於OPN基因的啟動子中鑑定出可受甲基化調控之CpG雙核酸位點 (CpG 1, CpG 13, and CpG 20)。我們進一步利用差異性甲基化雜合晶片(differentially methylated hybridization chip: DMH chip)來篩選於複製動物基因體中有變異的甲基化DNA片段,於心臟、耳朵及睪丸組織中皆有其基因甲基化變異,其中有五個基因,包括:EXD3, PDZD4, MTMR7, IGF2R, 和PEG3等基因,業經成功篩選並評估具有預測性差異甲基化片段作為後續的分析。值得一提的是PEG3蛋白,由於在複製豬五號的睪丸呈現無精症(azoospermia),吾人以免疫組織染色法來分析於正常豬及複製豬五號的睪丸中,其PEG3, NFκB, β-catenin, 及E-cadherin蛋白的表現及分布位置,結果證明其中E-cadherin及β-catenin蛋白分別係分布於複製豬五號睪丸的生精細管管腔邊緣(正常豬則分布在睪丸生精細管管腔內部),而PEG3蛋白則分布在複製豬五號睪丸生精細管管腔內部(正常豬則分布在生精細管管腔外部及萊氏細胞中),目前已知PEG3的存在會造成β-catenin的降解,而E-cadherin在細胞膜上能促進精原母細胞(spermatogonia)的移動功能,同樣也會受到β-catenin的調控,因此吾人推測PEG3蛋白的分布位置及表現的異常,可能是導致生精作用不全之一原因。進一步研究完成鑑定豬隻基因體中,四個銘印基因的主要差異性甲基化區域,分別為INS和IGF2 (母源性染色體銘印基因)及H19和IGF2R (父源性染色體銘印基因)。甲基化異常之現象,包括:高度甲基化 (hypermethylation)及低度甲基化(hypomethylation);在複製豬的基因體中其甲基化程度之變異比例,分別為:H19 (45% vs. 30%), IGF2 (40% vs. 0%), INS (50% vs. 5%), 和IGF2R (15% vs. 45%);在複製牛基因體中者,則為:H19 (0% vs. 29%), IGF2 (21% vs. 29%), 和XIST (7.9% vs. 7.9%)。目前對於大型哺乳類動物的銘印基因之研究報告甚少,本研究係透過甲基化銘印模式的分析,顯示複製豬及牛的銘印基因的甲基化異常的確是經常發生的現象。為謀瞭解此等甲基化修飾異常是否擴及其他染色體區域,進一步研究且完成分析四個衛星基因座(Satellite loci),包括:Satellite I, Satellite II, VNTR, 及Art2等,結果證明其甲基化差異性不大,研究顯示在銘印基因調控區及衛星片段調控區有著不同的甲基化調控機制。更進一步藉由即時定量聚合酶連鎖反應,觀察銘印基因在複製豬NT-6組織上的表現,結果顯示在複製豬的肝臟、靜脈、耳朵、皮膚及子宮等組織中,其IGF2及H19的表現分別均有過量表現的異常情形。總結前述試驗說明了即使複製成功且能長大為成體的豬或牛隻,其基因體中保留了在胚胎時期所獲得的異常甲基化銘印模式,雖然避免於分娩前即死亡的命運,但是此等異常甲基化的銘印模式,的確足以影響其出生後之存活時間或成體後呈現病徵之情事。總結本研究結果,證明在複製動物的產製過程中仍存在關於健康及導致非預期病症的風險,深入瞭解彼等在複製動物產製過程中銘印基因的異常甲基化變動並加以校正,顯然係未來改善核轉置動物複製技術的一個重要環節。

DNA methylation is a major epigenetic modification found in mammalian genomes and it regulates crucial aspects of gene functions. Mammal cloning by somatic cell nuclear transfer (SCNT) often results in gestational or neonatal failure with only a few percentage of manipulated embryos producing live births. Many of the cloned embryos that survive to term succumb to a variety of abnormalities that are likely due to inappropriate epigenetic reprogramming. The uniparentally expressed imprinted genes control the development of embryos. This study has shown the aberrant putative differentiated methylation regions (DMRs) of imprinted genes existed in the genome of cloned animal, even their appearance looks like normal. In this study, we firstly defined the several putative DMRs of imprinted genes in cloned porcine and bovine genomes. The putative DMRs of imprinted genes are vulnerable during somatic cell nuclear transfer (SCNT) process. The skipping of the reprogramming process happened in cloning animals by nuclear transfer of somatic cells may cause the inappropriate methylation patterns. The differentiated somatic cells, unlike germ cells, do not back to the necessary reprogramming process to erase the epigenetic markers correctly and timely. These abnormal modifications could affect the expression of genes and cause the unexpected pathologies. The OPN and H19 were identified by the multimeric methyl-binding domain (MBD) protein pull down assay. We also demonstrated three CpG sites (CpG1, CpG13, and CpG20) which regulate the OPN transcription by their DNA methylation status. In cloned pigs, these OPN and H19 genes showed aberrant methylation patterns in their ear tissues. Furthermore, differentially methylated hybridization chip (DMH chip) was also performed to screen the aberrant methylated DNA elements in cloned animals. Either hypermethylation or hypomethylation frequently appeared in the tissues of cloned animals. Five genes, EXD3, PDZD4, MTMR7, IGF2R, and PEG3 were selected for further study. Especially, the PEG3 with aberrant methylation status was selected from cloned pig CP5 testis with azoospermia phenomenon. The immunohistochemistry (IHC) staining of PEG3 showed the extremely different distribution in testis between wild-type (WT) and CP5 pigs. The PEG3 interacts with NF-κB, β-catenin, and E-cadherin. The data showed that CP5 testis lacked of the E-cadherin expression inside testicular cord. The aberrant location of PEG3 expression may affect the maturation of spermatogonia through the down-regulated β-catenin and E-cadherin. Connectively, we identified four DMRs of imprinted genes in the wild-type pig genomes, including two maternal imprinted loci (INS and IGF2) and two paternal imprinted loci (H19 and IGF2R). Aberrant DNA methylation phenomenon, either hypermethylation or hypomethylation, commonly appeared in H19 (45% vs. 30%), IGF2 (40% vs. 0%), INS (50% vs. 5%), and IGF2R (15% vs. 45%) imprinted loci, in cloned pigs and also found in cloned bovine genomes: H19 (0% vs. 29%), IGF2 (21% vs. 29%), XIST (7.9% vs. 7.9%). Our data also revealed that aberrant methylation frequently occurred in imprinted genes, but not satellite loci, Satellite I, Satellite II, VNTR, and Art2, in cloned bovine. It indicated that the methylation between imprinted genes and satellite loci is regulated by different mechanisms. Furthermore, quantitative RT-PCR was applied to assess the expression of these imprinted genes in the cloned bovine NT-6. We found that IGF2 and H19 extremely overexpressed in the liver, vein, ear, skin, and uterus of the NT-6 bovine. In conclustion, even the successful produced of cloned swine and bovine fortunately avoid the preneonatal or postnatal death, the perturbation and intervention of mehtylation in imprinted genes still exists. It perhaps may be the reasons of adult pathologies and short life occurred in cloned animals. Here, we provided the results that the cloned animals still have the several risks of health and unexpected defects. Finding and correcting the aberrant pattern of imprinted genes after SCNT would offer insights into the improvement in future cloning animal technique.
URI: http://hdl.handle.net/11455/20321
其他識別: U0005-2208201211193400
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