转录延伸因子ELL3在小鼠B细胞中的功能研究
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摘要
ELL3作为一个转录延伸因子,与ELL1和ELL2同属于ELL (eleven-nineteen lysine-rich leukemia gene)家族。ELL1和ELL2广泛表达于各组织,而ELL3特异性地在B细胞中表达。ELL3在体外可以促进RNA聚合酶合成RNA,而B细胞需要ELL3特异性的表达,ELL3在B细胞中是否有特殊的功能和靶基因尚不清楚。另外,体细胞超突变过程需要基因的转录,最近的研究发现转录的停滞会导致AID结合在停滞位点造成突变的集中。ELL3的敲除是否会影响体细胞超突变的突变模式和分布是我们关注的一个焦点问题。
为了解决以上问题,本论文研究建立了敲除ELL3的C57/B6小鼠,分析敲除小鼠的免疫系统的发育,结果发现ELL3敲除小鼠与野生型小鼠相比,B细胞和T细胞的发育没有显著差异。体内免疫反应检测显示,ELL3敲除小鼠的T细胞依赖的抗原抗体反应缺陷,而T细胞非依赖的抗原抗体反应止常。T细胞依赖的抗原免疫后,敲除小鼠产生的特异性免疫球蛋白含量与野生型相比降低,同时生发中心与野生型相比变小变少。由于ELL3在T细胞中不表达,可以推断敲除ELL3的小鼠影响了B细胞的功能造成了T细胞依赖的免疫反应缺陷。体外实验证实,ELL3敲除的B细胞在高剂量的anti-IgM的刺激下活细胞比例降低,表明在体内ELL3可能影响了B细胞的存活。生发中心B细胞的RNAseq结果表明,ELL3的敲除导致fos基因的表达上调,而fos转基因的小鼠已经证实fos的高表达引起生发中心B细胞的死亡。对T细胞依赖的免疫反应产生的免疫球蛋白进行体细胞超突变分析发现,JH4内含子区的突变频率在敲除小鼠中显著降低,而VH186.2由于生发中心选择压力,选择出特异性高的抗体造成了突变频率变化不大。ELL3敲除小鼠体细胞超突变的频率降低也与生发中心B细胞的死亡结果吻合,说明ELL3是影响T细胞依赖的免疫反应的重要因子。ELL3的缺失会造成T细胞依赖的免疫缺陷。
本论文的研究结果对未来部分临床免疫缺陷病的诊断有重要意义,同时也对研究转录延伸因子对免疫系统影响的基础研究有所帮助。
ELL3as an elongation factor belongs to ELL (eleven-nineteen lysine-rich leukemia gene) family which includes3members:ELL1, ELL2and ELL3. In contrast to ELL1and ELL2which are expressed ubiquitously, ELL3is highly and specifically expressed in B cells. Although ELL3could promote RNA synthesis through increasing RNA polymerase catalytic rate in vitro, the biological function of ELL3in vivo is not clear. Transcription is known to be indispensable for somatic hypermutation (SHM), and transcription pausing and stalling causes multiple clustered mutations by AID. As ELL3is specifically expressed in B cells, it is interesting to investigate whether ELL3plays a special role in B cells. The two major questions we set out to ask are:Is the ELL3involved in the SHM process? Does ELL3deficiency affect SHM (somatic hypermutation) pattern or distribution?
To address these questions, we generated ELL3knockout (KO) C57/B6mice. The development of B and T cells was normal in ELL3knock out mice. The KO mice showed a deficiency in responding to immunization of different doses of T-dependent antigen, whereas T-independent antigen immunization induced a normal immunoglobulin production. Consistent with T-dependent immune deficiency, the germinal center formation was impaired in ELL3KO mice. As ELL3is not expressed in T cells, it may affect T-dependent immune response through altering B cell functions.In vitro, live cell percentage decreased in ELL3KO B cells under high doses of anti-IgM stimulation, which may indicate that ELL3plays a role in B cell survival and cause germinal center death by changing expression of some specific genes. To find out the target genes of ELL3, we sequenced the transcriptome of germinal center B cells using RNA-seq, which revealed an up-regulation offos gene in ELL3KO mice. This is in accordance with a previous finding that fos over-expression caused B cell death in germinal center of fos transgenic mice. Furthermore, we analyzed the SHM after T-dependent immunization, showing that mutaion frequency of JH4intronic region was significantly decreased in KO mice, and the VH186.2mutation frequency was normal, which may be due to selection of high affinity antibody secreting cells in germinal center. The decrease of the JH4intronic mutations frequency was consistent with the germinal center death in KO mice. All these results together suggest that ELL3plays pivotal roles in T-dependent immune response and germinal center formation.
The findings reported in this thesis are helpful to understand how the transcription elongation factor is involved in the immune response, and may also help to improve the clinical diagnosis of specific category of immune deficiency.
为了解决以上问题,本论文研究建立了敲除ELL3的C57/B6小鼠,分析敲除小鼠的免疫系统的发育,结果发现ELL3敲除小鼠与野生型小鼠相比,B细胞和T细胞的发育没有显著差异。体内免疫反应检测显示,ELL3敲除小鼠的T细胞依赖的抗原抗体反应缺陷,而T细胞非依赖的抗原抗体反应止常。T细胞依赖的抗原免疫后,敲除小鼠产生的特异性免疫球蛋白含量与野生型相比降低,同时生发中心与野生型相比变小变少。由于ELL3在T细胞中不表达,可以推断敲除ELL3的小鼠影响了B细胞的功能造成了T细胞依赖的免疫反应缺陷。体外实验证实,ELL3敲除的B细胞在高剂量的anti-IgM的刺激下活细胞比例降低,表明在体内ELL3可能影响了B细胞的存活。生发中心B细胞的RNAseq结果表明,ELL3的敲除导致fos基因的表达上调,而fos转基因的小鼠已经证实fos的高表达引起生发中心B细胞的死亡。对T细胞依赖的免疫反应产生的免疫球蛋白进行体细胞超突变分析发现,JH4内含子区的突变频率在敲除小鼠中显著降低,而VH186.2由于生发中心选择压力,选择出特异性高的抗体造成了突变频率变化不大。ELL3敲除小鼠体细胞超突变的频率降低也与生发中心B细胞的死亡结果吻合,说明ELL3是影响T细胞依赖的免疫反应的重要因子。ELL3的缺失会造成T细胞依赖的免疫缺陷。
本论文的研究结果对未来部分临床免疫缺陷病的诊断有重要意义,同时也对研究转录延伸因子对免疫系统影响的基础研究有所帮助。
ELL3as an elongation factor belongs to ELL (eleven-nineteen lysine-rich leukemia gene) family which includes3members:ELL1, ELL2and ELL3. In contrast to ELL1and ELL2which are expressed ubiquitously, ELL3is highly and specifically expressed in B cells. Although ELL3could promote RNA synthesis through increasing RNA polymerase catalytic rate in vitro, the biological function of ELL3in vivo is not clear. Transcription is known to be indispensable for somatic hypermutation (SHM), and transcription pausing and stalling causes multiple clustered mutations by AID. As ELL3is specifically expressed in B cells, it is interesting to investigate whether ELL3plays a special role in B cells. The two major questions we set out to ask are:Is the ELL3involved in the SHM process? Does ELL3deficiency affect SHM (somatic hypermutation) pattern or distribution?
To address these questions, we generated ELL3knockout (KO) C57/B6mice. The development of B and T cells was normal in ELL3knock out mice. The KO mice showed a deficiency in responding to immunization of different doses of T-dependent antigen, whereas T-independent antigen immunization induced a normal immunoglobulin production. Consistent with T-dependent immune deficiency, the germinal center formation was impaired in ELL3KO mice. As ELL3is not expressed in T cells, it may affect T-dependent immune response through altering B cell functions.In vitro, live cell percentage decreased in ELL3KO B cells under high doses of anti-IgM stimulation, which may indicate that ELL3plays a role in B cell survival and cause germinal center death by changing expression of some specific genes. To find out the target genes of ELL3, we sequenced the transcriptome of germinal center B cells using RNA-seq, which revealed an up-regulation offos gene in ELL3KO mice. This is in accordance with a previous finding that fos over-expression caused B cell death in germinal center of fos transgenic mice. Furthermore, we analyzed the SHM after T-dependent immunization, showing that mutaion frequency of JH4intronic region was significantly decreased in KO mice, and the VH186.2mutation frequency was normal, which may be due to selection of high affinity antibody secreting cells in germinal center. The decrease of the JH4intronic mutations frequency was consistent with the germinal center death in KO mice. All these results together suggest that ELL3plays pivotal roles in T-dependent immune response and germinal center formation.
The findings reported in this thesis are helpful to understand how the transcription elongation factor is involved in the immune response, and may also help to improve the clinical diagnosis of specific category of immune deficiency.
引文
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