fat1 & fat2转基因牛胚胎的构建及早期克隆胚甲基化模式的研究
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摘要
转基因技术可以通过导入外源基因的方式人为地改造动物基因组,达到快速定向改造生物体的目地。在众多转基因方法中,核移植技术以其高效,快捷和低成本的突出优势,成为目前培育转基因动物的主要手段。但该技术仍存在一些问题,如大多数克隆动物在出生前就死亡,存活下来的克隆动物也常会伴有大量的表型异常和不同程度的发育缺陷。已有研究发现,该现象与体细胞移入去核的卵母细胞后进行异常的甲基化重编码程序有关。为了揭示核移植胚胎异常甲基化模式,本试验对5个发育阶段的早期核移植胚胎(合子期、S期、2-cell、8-cell和桑椹期)进行了抗-5mC抗体的免疫荧光检测,并对核移植胚胎中呈父源印记的IGF2/H19基因簇ICR区和呈母源印记的PWS/AS基因簇ICR区分别进行了bsp测序；同时试验还对10个参与甲基化重编程的重要因子在早期核移植胚发育过程中表达量的变化模式进行了定量研究,得出以下结论：
(1)本试验利用核移植技术首次成功构建了携带有fatl以及fat2基因的转基因西杂牛胚胎,转基因胚的阳性率为5.45%。通过荧光检测可见卵泡外周有密集强烈的荧光表现,说明转入的外源基因成功翻译蛋白并且集结于卵泡染色质密集的部位。
(2) SCNT胚的父源基因组在S期之前极微弱的发生了主动去甲基化,伴随着DNA复制的开始,又发生了微弱的被动去甲基化。8-cell以后,SCNT胚胎父源基因组与IVF胚父源基因组的甲基化重建能力相当。
(3)早期胚胎中,S期发生了多种甲基化印记激活与抑制的调控过程,但在SCNT胚胎中类似Dnmt3a和Dnmt3b等促进甲基化作用因子表达量的提高及功能的增强占了主导地位,这使得母源DNA过早的进行了甲基化的重建造成了克隆胚胎的甲基化过高。
(4) SCNT胚胎中MBD1、 Mecp2和MBD3三种甲基化结合蛋白在S期高水平表达,维持了供体核基因组的甲基化状态,影响了基因组的正常去甲基化机制。另外,克隆胚胎大量出现发育异常或死胎现象与MBD4基因表达下调引起基因错配有一定关系。
(5)SCNT胚胎中2-cell之前去甲基化能力的显著下降并不是单方面由促甲基化酶表达量升高引起的,一些去甲基化调节因子(如AID以及APOBEC1等基因)的低表达也在一定程度上阻碍了克隆胚胎基因组去甲基化的进行。试验还发现,所有促进甲基化作用的细胞因子并不是在染色体的所有区段都是同向作用的,在某些特定靶点其作用会发生逆转。
The introduction and expression of exogenous gene in animal by genetic transformation is now the efficient way to reform organism. The somatic cell nuclear transfer (SCNT) has been wide applied in production of transgenic animal, due to the high performance and the low cost. However, cloning by somatic cell nuclear transfer (SCNT) is still inefficient. During development, a significant number of cloned embryos die during the pre-and peri-implantation period. This phenomenon is associated with the abnormal reprogramming of the donor nucleus. In order to study the methylating pattern of clone embryos, we detect5stages of clone early embryos (zygophase, S phase,2-cell,8-cell and morula) by immunofluorescence with antibodies against5-methylcytosine (5mC), and research the methylating pattern of the ICRs for PWS/AS imprinting cluster and IGF2/H19imprinting cluster by bisulfite sequencing PCR (bsp). We also detect10genes, which participated in the regulation of methylating by FQ-RT-PCR. The results of array analysis are as follows:
(1) In our study, we product the early embryos which carried the fat-1and the fat-2gene for the fist time, the positive rate is5.45%. We also examine the transgenes embryos by fluorescence microscope, there are strong signals everywhere in the blastocysts especially in the periphery of blastocysts. Therefore the blastocysts which carried the exogenous gene could be used to embryo transfer.
(2) The actively demethylation of paternal germline is very weak before cleavage in clone early embryos, and the ability of de novo methylation after8-cell is the same as IVF embryos.
(3) In early clone early embryos, the de novo methylation has started before S phase ahead of IVF embryos. There are many over expression and tonic enzymes as Dnmt3a and Dnmt3b in clone early embryos, which promote de novo methylation before S phase.
(4) The over expression of MBD1, Mecp2and MBD3lead to the high level of methylation in S phase. In addition, the low expression of MBD4could lead to cloned embryos die during the pre-and peri-implantation period, because of mismatches.
(5) The low expression of AID gene and APOBEC1gene are responsible for incomplete demethylation in clone early embryos. Otherwise, same enzymes, which always promote de novo methylation, could inhibit methylation in same specific target point.
(1)本试验利用核移植技术首次成功构建了携带有fatl以及fat2基因的转基因西杂牛胚胎,转基因胚的阳性率为5.45%。通过荧光检测可见卵泡外周有密集强烈的荧光表现,说明转入的外源基因成功翻译蛋白并且集结于卵泡染色质密集的部位。
(2) SCNT胚的父源基因组在S期之前极微弱的发生了主动去甲基化,伴随着DNA复制的开始,又发生了微弱的被动去甲基化。8-cell以后,SCNT胚胎父源基因组与IVF胚父源基因组的甲基化重建能力相当。
(3)早期胚胎中,S期发生了多种甲基化印记激活与抑制的调控过程,但在SCNT胚胎中类似Dnmt3a和Dnmt3b等促进甲基化作用因子表达量的提高及功能的增强占了主导地位,这使得母源DNA过早的进行了甲基化的重建造成了克隆胚胎的甲基化过高。
(4) SCNT胚胎中MBD1、 Mecp2和MBD3三种甲基化结合蛋白在S期高水平表达,维持了供体核基因组的甲基化状态,影响了基因组的正常去甲基化机制。另外,克隆胚胎大量出现发育异常或死胎现象与MBD4基因表达下调引起基因错配有一定关系。
(5)SCNT胚胎中2-cell之前去甲基化能力的显著下降并不是单方面由促甲基化酶表达量升高引起的,一些去甲基化调节因子(如AID以及APOBEC1等基因)的低表达也在一定程度上阻碍了克隆胚胎基因组去甲基化的进行。试验还发现,所有促进甲基化作用的细胞因子并不是在染色体的所有区段都是同向作用的,在某些特定靶点其作用会发生逆转。
The introduction and expression of exogenous gene in animal by genetic transformation is now the efficient way to reform organism. The somatic cell nuclear transfer (SCNT) has been wide applied in production of transgenic animal, due to the high performance and the low cost. However, cloning by somatic cell nuclear transfer (SCNT) is still inefficient. During development, a significant number of cloned embryos die during the pre-and peri-implantation period. This phenomenon is associated with the abnormal reprogramming of the donor nucleus. In order to study the methylating pattern of clone embryos, we detect5stages of clone early embryos (zygophase, S phase,2-cell,8-cell and morula) by immunofluorescence with antibodies against5-methylcytosine (5mC), and research the methylating pattern of the ICRs for PWS/AS imprinting cluster and IGF2/H19imprinting cluster by bisulfite sequencing PCR (bsp). We also detect10genes, which participated in the regulation of methylating by FQ-RT-PCR. The results of array analysis are as follows:
(1) In our study, we product the early embryos which carried the fat-1and the fat-2gene for the fist time, the positive rate is5.45%. We also examine the transgenes embryos by fluorescence microscope, there are strong signals everywhere in the blastocysts especially in the periphery of blastocysts. Therefore the blastocysts which carried the exogenous gene could be used to embryo transfer.
(2) The actively demethylation of paternal germline is very weak before cleavage in clone early embryos, and the ability of de novo methylation after8-cell is the same as IVF embryos.
(3) In early clone early embryos, the de novo methylation has started before S phase ahead of IVF embryos. There are many over expression and tonic enzymes as Dnmt3a and Dnmt3b in clone early embryos, which promote de novo methylation before S phase.
(4) The over expression of MBD1, Mecp2and MBD3lead to the high level of methylation in S phase. In addition, the low expression of MBD4could lead to cloned embryos die during the pre-and peri-implantation period, because of mismatches.
(5) The low expression of AID gene and APOBEC1gene are responsible for incomplete demethylation in clone early embryos. Otherwise, same enzymes, which always promote de novo methylation, could inhibit methylation in same specific target point.
引文
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