NSPc1沉默HOX基因的表观遗传学机制研究
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摘要
Polycomb家族蛋白(Polycomb group proteins,PcGs)在进化中高度保守,存在于几乎所有细胞中,在胚胎发育、胚胎干细胞和成体干细胞状态的维持、细胞命运决定以及肿瘤形成等过程中起非常重要的作用。NSPcl(Nervous System Polycomb 1,又名PCGF1,Polycomb group ring finger 1)是于2001年分离、鉴定的PcG家族的一个新基因,与哺乳动物PcG家族成员MEL18,BMI1具有较高同源性。然而,无论在功能还是在作用机制方面,NSPc1都相对缺乏研究。曾有报告指出,NSPc1在多种肿瘤中高表达;我们前期的工作结果表明,过表达NSPc1能促进肿瘤细胞增殖;相反,NSPc1敲低的肿瘤细胞则表现为生长缓慢、接触抑制。本论文重点对NSPc1抑制靶基因转录、调控细胞增殖的分子机制进行了研究。
首先,我们尝试纯化NSPc1功能性复合体,同时已经有文献报道,通过串联亲和纯化(Tandem Affinity Purification,TAP)的方法,研究者发现NSPc1和其它PcG家族成员RING1,RING2,RYBP处于同一复合体中。通过免疫共沉淀(Coimmunoprecipitation,CoIP)实验,我们验证了NSPc1和RING2的相互作用。这一复合体与此前报道的组蛋白H2A泛素化复合体(human Polycomb repressive complex 1-like,hPRC1L)很相似:其中RING2具有泛素E3连接酶活性,BMI1等增强其活性,从而促进H2A泛素化。同样地,在HeLa细胞敲低NSPc1之后,细胞内泛素化H2A(uH2A)整体水平明显下降;相反,过表达NSPc1能促进H2A泛素化;并且体外重组NSPc1蛋白能显著增强RING2的活性。因此,NSPc1有可能通过促进组蛋白H2A泛素化而抑制靶基因的转录。
PcG家族蛋白通常通过调控HOX基因的转录而影响体节发育,因此,我们在HeLa和NT2/D1(人胚胎肿瘤细胞)细胞中通过RT-PCR的方法筛选了NSPc1可能抑制的HOX基因。结果表明,在NSPc1敲低的细胞中,HOXA7和HOXB13表达上调较为明显。为了验证NSPc1介导的H2A泛素化是否参与这两个HOX基因的转录抑制,我们在它们的上游进行了染色质免疫沉淀实验(Chromatin Immunoprecipitation,ChIP)。实验结果显示,NSPc1复合体确实结合于它们的启动子区,并且当NSPc1敲低之后,RING2在相应区域的结合减少,组蛋白H2A泛素化水平显著下降,基本验证了我们的设想。
PcGs蛋白在细胞内多以复合体的形式起作用,至少可以分为两大类:起始复合体(Polycomb Repressive Complex 2,PRC2)和维持复合体(Polycomb RepressiveComplex 1,PRC1),其中PRC2成员EZH2能引起组蛋白H3K27三甲基化(H3K27trimethylation,me3H3K27),这一修饰又能募集PRC1复合体进一步维持靶基因的转录抑制。近年来研究还发现,PcGs的转录抑制效应与DNA甲基化(DNA methylation)紧密相关,而后者也是参与基因转录抑制的一种重要的表观遗传学修饰形式,在哺乳动物细胞内由DNA甲基转移酶(DNA methyltransferases,DNMTs)DNMT1负责维持DNA甲基化。通过RT-PCR实验,我们发现PRC2成员EZH2或DNA甲基转移酶DNMT1敲低、或5-aza-dC(一种DNMTs抑制剂)处理的HeLa细胞中,HOXA7的表达也去抑制,即EZH2和DNA甲基化也参与了HOXA7基因的沉默。
接下来,我们致力于揭示PcGs介导的组蛋白修饰与DNA甲基化如何协调而参与HOX基因沉默。通过ChIP和基因组亚硫酸氢盐修饰后测序(Bisulfite sequencing)实验,我们发现:在HeLa细胞中当PRC2成员EZH2敲低之后,将导致DNA甲基转移酶DNMT1和PRC1成员NSPc1在HOXA7和HOXB13基因启动子区的结合都明显减少;而敲低NSPc1之后,EZH2的募集和me3H3K27水平不受影响,但是DNMT1结合却被显著抑制,并且相应的DNA甲基化的水平也明显下降;敲低DNMT1或者用其抑制剂5-aza-dC处理细胞,EZH2结合没有变化,但NSPc1结合减少。因此,在HOX基因沉默过程中,EZH2介导的me3H3K27募集NSPc1/RING2复合体,后者促进相应区域的H2A泛素化;同时,EZH2可以直接募集DNA甲基转移酶DNMTs,起始并维持相应CpG岛的DNA甲基化;而下游的H2A泛素化及DNA甲基化这两种表观遗传学修饰之间不是孤立的,而是相互依赖(interdependent)的,因为无论干扰NSPc1还是DNMT1都会影响到对方在靶基因调控区的结合和功能,使靶基因去抑制,即它们协同作用,维持HOX靶基因的稳定、长期、不可逆的沉默。
本论文揭示了PcG家族蛋白NSPc1的一种转录调控模式,这一模式与近年来提出的肿瘤发生的表观遗传学机制相似,建立了NSPc1与其它表观遗传调节因子(如其它PcG蛋白和DNMTs)在细胞增殖、肿瘤发生过程中的联系。并且,其中对调节HOX靶基因转录的研究,为进一步阐明NSPc1在胚胎发育过程中的作用奠定了基础。
Polycomb group proteins (PcG) are highly conserved from Drosophila, C. elegans to human. They are expressed in almost all cell types and play essential roles in embryonic development, cell memory and cell fate decision. PcGs are widely studied about the function in the maintenance of embryonic stem (ES) cells or adult stem cells and tumorigenesis in recent years. Novel PcG gene NSPc1 (Nervous System Polycomb 1, also named as Polycomb group RING finger 1, PCGF1) is homologous to the family members BMI1 and MEL18 in mammals, but less well studied. It was ever reported that NSPc1 is expressed higher in several types of tumors than in the normal tissues. Our previous results also demonstrated that NSPc1 promoted the tumor cell proliferation. This thesis focuses on the studies of mechanism for NSPc1 in transcriptional repression and cell proliferation regulation.
We first purified NSPc1 functional repressive complex. But before we detected the purified sample by Mass Spectrometry, the results were published that Tandem Affinity Purification (TAP) showed that NSPc1 and other PcG family members like RING1, RING2 and RYBP co-eluted in the same complex. And their interactions were verified by Co-immunoprecipitation (CoIP) assay. This complex is highly similar to the human Polycomb Repressive Complex-1 Like (hPRC1L) which turned out to ubiquitinate histone H2A. Among the hPRC1L components, RING2 is the main E3 ligase, while other PcG members like BMI1 stimulate its activity. Similarly, we found that the NSPc1 complex also could ubiquitinate H2A. When NSPc1 was knocked down in HeLa cells, the global level of uH2A was reduced. On the contrary, NSPc1 overexpression promoted H2A ubiquitination. Though NSPc1 recombinant protein alone failed to ubiquitinate H2A, it dose-dependently enhanced the E3 ligase activity of RING2. CoIP assay showed that NSPc1 could interact both RING2 and H2A, probably stabilizing the ubiqutination reaction as a bridge. Therefore NSPc1 probably represses target genes transcription through mediating H2A ubiquitination.
To test this hypothesis, we carried out Chromatin Immunoprecipitation (ChIP) experiment on specific target genes. Given that PcG proteins are known to regulate HOX gene expression and therefore the body segment development, we screened the potential target HOX genes for NSPc1 by RT-PCR: HOXA7 and HOXB13 were significantly derepressed in NSPc1 knockdown HeLa and NT2/D1 cells. Therefore these two target genes were chosen for further experiments. First, ChIP assay demonstrated that NSPc1 complex did bind to their promoter regions. And deficiency of NSPc1 resulted in reduced association with RING2 and significant decrease of H2A ubiquitination in the region, which supported the idea that NSPc1-mediated H2A ubiquitination was responsible for its transcriptional repression effect.
PcG proteins regulate gene expression by forming large multiprotein complexes, which can at least be divided into two principal types: the maintenance complex (PRC2) and initiate complex (PRC1). PRC2 is catalytically active to trimethylate H3K27. And the H3K27 tnmethylation (me3H3K27) can recruit PRC1. Recent studies have also demonstrated that PcG proteins are closely connected with DNA methylation, which is another important transcriptionally repressive epigenetic modification. RT-PCR experiment also showed that H0XA7 expression derepression was also found in EZH2 and DNMT1 knockdown HeLa cells, as well as in 5-aza-dC (a potent DNA methyltransferase inhibitor) treated HeLa cells. Therefore EZH2-mediated H3K27 trimethylation and DNA methylation are also involved in HOX gene silencing.
Then how all these epigenetic modifications coordinate to keep HOX genes silenced? ChIP experiment in HeLa cells showed that loss of NSPc1 binding and DNMT1 deficiency did not affect EZH2 recruitment and H3K27 trimethylation. But EZH2 depletion resulted in reduced EZH2 binding and H3K27 trimethylation, concomitant with a significant reduction of NSPc1 binding and H2A ubiquitination, and loss of DNMT1 recruitment. Collectively, NSPc1 and DNMT1 recruitment, H2A ubiquitination and DNA methylation are downstream events of EZH2-mediated H3K27 trimethylation. Interestingly, the knockdown of NSPc1 resulted in loss of DNMT1 binding and DNA hypomethylation examined by Bisulfite Sequencing, while the knockdown of DNMT1 or 5-aza-dCtreatment also affected NSPc1 recruitment. Therefore DNA methylation andNSPc1-mediated H2A ubiquitination are not separated, but interdependent and self-reinforce each other in HOX gene silencing.
ChIP-on-chip assays have demonstrated the stem cell PcG targets are more vulnerable than non-targets to DNA hypermethylation, turning the reversible state to permanent silencing, and thereby locking stem/precursor cells into abnormal c1onal expansion which predispose to cancer. Hence our extablished epigenetic network has partially demonstrated the transcriptional repression mechanism for NSPc1 and established a functional link of NSPc1 with different chromatin modifers in tumorigenesis. The research into HOX gene expression regulation in this thesis will also help to further elucidate the function of NSPc1 in embryonic development.
首先,我们尝试纯化NSPc1功能性复合体,同时已经有文献报道,通过串联亲和纯化(Tandem Affinity Purification,TAP)的方法,研究者发现NSPc1和其它PcG家族成员RING1,RING2,RYBP处于同一复合体中。通过免疫共沉淀(Coimmunoprecipitation,CoIP)实验,我们验证了NSPc1和RING2的相互作用。这一复合体与此前报道的组蛋白H2A泛素化复合体(human Polycomb repressive complex 1-like,hPRC1L)很相似:其中RING2具有泛素E3连接酶活性,BMI1等增强其活性,从而促进H2A泛素化。同样地,在HeLa细胞敲低NSPc1之后,细胞内泛素化H2A(uH2A)整体水平明显下降;相反,过表达NSPc1能促进H2A泛素化;并且体外重组NSPc1蛋白能显著增强RING2的活性。因此,NSPc1有可能通过促进组蛋白H2A泛素化而抑制靶基因的转录。
PcG家族蛋白通常通过调控HOX基因的转录而影响体节发育,因此,我们在HeLa和NT2/D1(人胚胎肿瘤细胞)细胞中通过RT-PCR的方法筛选了NSPc1可能抑制的HOX基因。结果表明,在NSPc1敲低的细胞中,HOXA7和HOXB13表达上调较为明显。为了验证NSPc1介导的H2A泛素化是否参与这两个HOX基因的转录抑制,我们在它们的上游进行了染色质免疫沉淀实验(Chromatin Immunoprecipitation,ChIP)。实验结果显示,NSPc1复合体确实结合于它们的启动子区,并且当NSPc1敲低之后,RING2在相应区域的结合减少,组蛋白H2A泛素化水平显著下降,基本验证了我们的设想。
PcGs蛋白在细胞内多以复合体的形式起作用,至少可以分为两大类:起始复合体(Polycomb Repressive Complex 2,PRC2)和维持复合体(Polycomb RepressiveComplex 1,PRC1),其中PRC2成员EZH2能引起组蛋白H3K27三甲基化(H3K27trimethylation,me3H3K27),这一修饰又能募集PRC1复合体进一步维持靶基因的转录抑制。近年来研究还发现,PcGs的转录抑制效应与DNA甲基化(DNA methylation)紧密相关,而后者也是参与基因转录抑制的一种重要的表观遗传学修饰形式,在哺乳动物细胞内由DNA甲基转移酶(DNA methyltransferases,DNMTs)DNMT1负责维持DNA甲基化。通过RT-PCR实验,我们发现PRC2成员EZH2或DNA甲基转移酶DNMT1敲低、或5-aza-dC(一种DNMTs抑制剂)处理的HeLa细胞中,HOXA7的表达也去抑制,即EZH2和DNA甲基化也参与了HOXA7基因的沉默。
接下来,我们致力于揭示PcGs介导的组蛋白修饰与DNA甲基化如何协调而参与HOX基因沉默。通过ChIP和基因组亚硫酸氢盐修饰后测序(Bisulfite sequencing)实验,我们发现:在HeLa细胞中当PRC2成员EZH2敲低之后,将导致DNA甲基转移酶DNMT1和PRC1成员NSPc1在HOXA7和HOXB13基因启动子区的结合都明显减少;而敲低NSPc1之后,EZH2的募集和me3H3K27水平不受影响,但是DNMT1结合却被显著抑制,并且相应的DNA甲基化的水平也明显下降;敲低DNMT1或者用其抑制剂5-aza-dC处理细胞,EZH2结合没有变化,但NSPc1结合减少。因此,在HOX基因沉默过程中,EZH2介导的me3H3K27募集NSPc1/RING2复合体,后者促进相应区域的H2A泛素化;同时,EZH2可以直接募集DNA甲基转移酶DNMTs,起始并维持相应CpG岛的DNA甲基化;而下游的H2A泛素化及DNA甲基化这两种表观遗传学修饰之间不是孤立的,而是相互依赖(interdependent)的,因为无论干扰NSPc1还是DNMT1都会影响到对方在靶基因调控区的结合和功能,使靶基因去抑制,即它们协同作用,维持HOX靶基因的稳定、长期、不可逆的沉默。
本论文揭示了PcG家族蛋白NSPc1的一种转录调控模式,这一模式与近年来提出的肿瘤发生的表观遗传学机制相似,建立了NSPc1与其它表观遗传调节因子(如其它PcG蛋白和DNMTs)在细胞增殖、肿瘤发生过程中的联系。并且,其中对调节HOX靶基因转录的研究,为进一步阐明NSPc1在胚胎发育过程中的作用奠定了基础。
Polycomb group proteins (PcG) are highly conserved from Drosophila, C. elegans to human. They are expressed in almost all cell types and play essential roles in embryonic development, cell memory and cell fate decision. PcGs are widely studied about the function in the maintenance of embryonic stem (ES) cells or adult stem cells and tumorigenesis in recent years. Novel PcG gene NSPc1 (Nervous System Polycomb 1, also named as Polycomb group RING finger 1, PCGF1) is homologous to the family members BMI1 and MEL18 in mammals, but less well studied. It was ever reported that NSPc1 is expressed higher in several types of tumors than in the normal tissues. Our previous results also demonstrated that NSPc1 promoted the tumor cell proliferation. This thesis focuses on the studies of mechanism for NSPc1 in transcriptional repression and cell proliferation regulation.
We first purified NSPc1 functional repressive complex. But before we detected the purified sample by Mass Spectrometry, the results were published that Tandem Affinity Purification (TAP) showed that NSPc1 and other PcG family members like RING1, RING2 and RYBP co-eluted in the same complex. And their interactions were verified by Co-immunoprecipitation (CoIP) assay. This complex is highly similar to the human Polycomb Repressive Complex-1 Like (hPRC1L) which turned out to ubiquitinate histone H2A. Among the hPRC1L components, RING2 is the main E3 ligase, while other PcG members like BMI1 stimulate its activity. Similarly, we found that the NSPc1 complex also could ubiquitinate H2A. When NSPc1 was knocked down in HeLa cells, the global level of uH2A was reduced. On the contrary, NSPc1 overexpression promoted H2A ubiquitination. Though NSPc1 recombinant protein alone failed to ubiquitinate H2A, it dose-dependently enhanced the E3 ligase activity of RING2. CoIP assay showed that NSPc1 could interact both RING2 and H2A, probably stabilizing the ubiqutination reaction as a bridge. Therefore NSPc1 probably represses target genes transcription through mediating H2A ubiquitination.
To test this hypothesis, we carried out Chromatin Immunoprecipitation (ChIP) experiment on specific target genes. Given that PcG proteins are known to regulate HOX gene expression and therefore the body segment development, we screened the potential target HOX genes for NSPc1 by RT-PCR: HOXA7 and HOXB13 were significantly derepressed in NSPc1 knockdown HeLa and NT2/D1 cells. Therefore these two target genes were chosen for further experiments. First, ChIP assay demonstrated that NSPc1 complex did bind to their promoter regions. And deficiency of NSPc1 resulted in reduced association with RING2 and significant decrease of H2A ubiquitination in the region, which supported the idea that NSPc1-mediated H2A ubiquitination was responsible for its transcriptional repression effect.
PcG proteins regulate gene expression by forming large multiprotein complexes, which can at least be divided into two principal types: the maintenance complex (PRC2) and initiate complex (PRC1). PRC2 is catalytically active to trimethylate H3K27. And the H3K27 tnmethylation (me3H3K27) can recruit PRC1. Recent studies have also demonstrated that PcG proteins are closely connected with DNA methylation, which is another important transcriptionally repressive epigenetic modification. RT-PCR experiment also showed that H0XA7 expression derepression was also found in EZH2 and DNMT1 knockdown HeLa cells, as well as in 5-aza-dC (a potent DNA methyltransferase inhibitor) treated HeLa cells. Therefore EZH2-mediated H3K27 trimethylation and DNA methylation are also involved in HOX gene silencing.
Then how all these epigenetic modifications coordinate to keep HOX genes silenced? ChIP experiment in HeLa cells showed that loss of NSPc1 binding and DNMT1 deficiency did not affect EZH2 recruitment and H3K27 trimethylation. But EZH2 depletion resulted in reduced EZH2 binding and H3K27 trimethylation, concomitant with a significant reduction of NSPc1 binding and H2A ubiquitination, and loss of DNMT1 recruitment. Collectively, NSPc1 and DNMT1 recruitment, H2A ubiquitination and DNA methylation are downstream events of EZH2-mediated H3K27 trimethylation. Interestingly, the knockdown of NSPc1 resulted in loss of DNMT1 binding and DNA hypomethylation examined by Bisulfite Sequencing, while the knockdown of DNMT1 or 5-aza-dCtreatment also affected NSPc1 recruitment. Therefore DNA methylation andNSPc1-mediated H2A ubiquitination are not separated, but interdependent and self-reinforce each other in HOX gene silencing.
ChIP-on-chip assays have demonstrated the stem cell PcG targets are more vulnerable than non-targets to DNA hypermethylation, turning the reversible state to permanent silencing, and thereby locking stem/precursor cells into abnormal c1onal expansion which predispose to cancer. Hence our extablished epigenetic network has partially demonstrated the transcriptional repression mechanism for NSPc1 and established a functional link of NSPc1 with different chromatin modifers in tumorigenesis. The research into HOX gene expression regulation in this thesis will also help to further elucidate the function of NSPc1 in embryonic development.
引文
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