PRMT1通过对MyoD精氨酸甲基化修饰调控成肌细胞分化
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摘要
表观遗传学是指在基因的DNA序列不发生改变的情况下,基因的表达水平与功能发生改变,并产生可遗传的表型组,主要包括DNA甲基化、组蛋白修饰、染色质重塑、RNA介导的调控。组蛋白修饰是表观遗传学中很重要的调控方式。包括组蛋白的甲基化、乙酰化、磷酸化、泛素化等,它对基因的激活和抑制起着重要作用。
MyoD是碱性螺旋-环-螺旋(basic helix-loop-helix, bHLH)家族的一个重要蛋白,在肌肉分化过程中起关键作用。我们以低血清诱导小鼠C2C12细胞作为肌肉分化的模型,并对其分化机制以及分化过程中早期分化标志—myogenin基因启动子区转录相关因子的结合进行研究,特别是精氨酸甲基转移酶修饰对myogenin基因表达调控机制。
C2C12细胞,主要呈三角形和纺锤形,少数多边形；而低血清诱导处理后,C2C12细胞逐渐呈现典型的分化形态,如胞体伸长,出现多核肌纤维类似结构并整齐排列等。我们利用甲基转移酶抑制剂AdOx处理C2C12细胞后发现,C2C12细胞的分化受到抑制。包括细胞形态学上不能出现多核肌纤维类似结构,分化标志myogenin的蛋白水平及mRNA水平的抑制。而组蛋白修饰酶PRMT1、PCAF及CARM1的蛋白质水平在药物处理前后变化不明显。表明甲基化修饰可能是肌肉分化过程中的必需过程。
双荧光素酶报告基因分析发现,在转染的各PRMT家族成员中,PRMT1和CARM1显著地增强myogenin基因启动子活性。我们进一步共转染组蛋白乙酰基转移酶PCAF、当PRMT1与CARM1及PCAF共转染时,比单独转染三者任何一个,或二二组合,激活效应更明显。说明PRMT1可与CARM1及PCAF协同激活MyoD介导的myogenin基因启动子活性。PRMT1是肌肉分化主导开关(master switch) MyoD的转录共激活子。
染色质免疫沉淀(Chromatin Immunoprecipitation, ChIP)分析是近些年发展起来检测蛋白因子在体内与染色质的结合,进而为蛋白因子参与染色质水平基因转录调控提供证据的方法。本研究运用该方法,检测了低血清诱导的C2C12细胞分化过程中,肌细胞分化决定因子MyoD、乙酰转移酶PCAF与精氨酸甲基转移酶CARM1及PRMT1在myogenin基因启动子区染色质的结合情况。这些转录因子在诱导3h后即可结合到染色质。
GST-pulldown实验显示,MyoD与PRMT1共存于一个复合物中。我们进一步确定了MyoD的氨基端及bHLH结构域与PRMT1相互作用,而MyoD的羧基端(MyoD162-318)则不能与PRMT1相互作用。将MyoD亚克隆至pEGFP-C1表达绿色荧光蛋白标签的融合蛋白,将PRMT1克隆至pmCherry-C1载体表达带红色荧光蛋白标签的融合蛋白。将GFP融合的MyoD与Cherry融合的PRMT1共转染C2C12细胞,48h后用激光扫描共聚焦荧光显微镜观察。我们发现,GFP-MyoD主要定位于核内,而Cherry-PRMT1则在整个细胞广泛分布,将二者荧光融合(merge)发现,绿色荧光的MyoD与红色荧光的PRMT1在细胞核内很好的融合为黄色,说明二者在细胞核内定位于相同位置。
我们通过体外GST-pulldown实验以及体内免疫共沉淀(CoIP)实验证实CARM1和PCAF共存于一个复合物中,并且这种相互作用不受AdOx抑制剂的影响的。通过分子生物学手段,我们进一步找到两者的具体结合部位。其中CARM1的催化结构域及C端结构域可与PCAF相互作用,而PCAF主要是通过HAT结构域(PCAF352-658)与CARM1相互作用。
利用体外甲基化反应体系及放射性自显影技术,我们首次发现PRMT家族酶的各个成员,只有PRMT1可甲基化修饰MyoD的精氨酸残基。为了确定MyoD甲基化修饰在细胞内是不是也发生,我们将带Flag标签的MyoD转染HEK 293T细胞,标记3H-甲硫氨酸(3H-Met)的同时加入蛋白质合成抑制剂。免疫亲和沉淀Flag-MyoD,放射自显影。结果显示,MyoD在细胞内存在甲基化修饰,并且AdOx可以抑制MyoD的甲基化修饰。为了确定MyoD的甲基化修饰位点,我们在细菌中表达并纯化了MyoD的N端及C端的删切突变体,加入GST-PRMT1后进行体外甲基化反应并放射性自显影,结果显示MyoD的甲基化修饰位点位于氨基酸162-318之间,即bHLH及C端结构域。
为了确定MyoD甲基化修饰的精确位点,我们在体外用PRMT1甲基化修饰MyoD,ESI质谱鉴定得到带两个电荷且质荷比为910.36的MyoD片段,即RQNGYDTAYYSEAVR(氨基酸221-235),二级质谱鉴定得到上述片段的第一个精氨酸(全长MyoD的221位精氨酸)存在双甲基化修饰。
综上结果,我们认为PRMT1对C2C12细胞的诱导分化过程中具有正调节作用。通过该类酶促的蛋白质精氨酸甲基化,以及其他调节因子对组蛋白的修饰或转录因子的活化,可有效地促进myogenin基因表达,并导致C2C12细胞的分化。我们首次发现PRMT1可甲基化修饰MyoD的精氨酸残基,深入研究PRMT1的调控机制有助于对肌肉细胞诱导分化机制的理解。
Epigenetics is the study of stable alternation in gene expression and function without changing DNA sequence and leading to inheritable phenotype, mainly including DNA methylation, histone modification, chromatin remodeling and non-coding RNA-mediated regulation. Histone modifications including histone methylation, acetylation, phosphorylation and ubiquitination play crucial roles in gene activation and inactivation.
MyoD, one of bHLH protein, play a crucial role in muscle differentiation. In our experiments, Low serum medium was used to induce C2C12 cells to differentiate, and the differentiation mechanism and the binding of associated transcription factors and chromatin modifying enzymes, especially protein arginine methyltransferase 1 to the myogenin promoter were investigated.
The morphology of C2C12 cells are triangular or spindly, and fewer are polygonal. After transferred to low serum medium, the C2C12 cells align regularly and acquire typical myogenic modality gradually, such as a more elongated shape, and multinucleated myofiber-like structure. when the C2C12 cells are treated with adenosine dialdehyde (AdOx) to block the PRMT, Low serum medium induced C2C12 cells differentiation was inhibit. The morphology of C2C12 cells are more big and don't present a multinucleated myofiber-like structure. Moreover, the increase of protein level and mRNA of myogenin was prevented by AdOx during C2C12 cells differentiation. In contrast, the protein level of PRMT1, PCAF and CARM1 was not changed during C2C12 cells differentiation in the presence of AdOx. These data indicate that arginie methylation is involved in muscle differentiation.
Dual-luciferase reporter assay showed that PRMT1 and CARM1 can enhanced the myogenin gene reporter activity when we transfected the C2C12 cells with each member of PRMTs. We further co-transfected C2C12 cells with PRMT1, CARM1 and PCAF, the myogenin gene reporter activity assays showed that PRMT1 synergistically coactivates together with CARM1 and PCAF MyoD-mediated transcription at the myogenin promoter.
Chromatin Immunoprecipitation (ChIP) assay was developed in recent years to detect protein factors that bind to chromatin. The binding of MyoD, PRMT1, PCAF and CARM1 to the myogenin promoter in control or differentiated C2C12 cells induced by low serum medium was studied by this method. We found that these factors were recruited on the myogenin gene promoter after induced for 3 hours in the low serum medium.
In vitro GST-pulldown assays showed that MyoD and PRMT1 exist in a complex, And the binding domain required for the interaction between MyoD and PRMT1 was determined, while the C-terminal domain of MyoD don't interact with PRMTl. We further subcloned MyoD into pEGFP-C1 and PRMT1 into pmCherry-C1, which express GFP-MyoD and Cherry-PRMT1 respectively. When C2C12 were co-transfected with these fusion protein plasmids, MyoD and PRMT1 were visualized by autofluorescence (green) of GFP and (red) of Cherry with a confocal microscopy, respectively. Green fluorescence of GFP-MyoD and red fluorescence of Cherry-PRMT1 merge well (yellow) in nucleus.
To demonstrate the direct interaction between CARM1 with PCAF, the in vitro and in vivo binding assays were done. And the binding domain required for the interaction between CARM1 and PCAF was determined. C-terminal domain of CARM1 (CARM11-141) can not interacts with PCAF, and PCAF HAT (histone acetyltransferase) domain interacts with CARM1.
In vitro methylation reaction assay and autoradiography indicated that, among the members of protein arginine methyltransferase family, only PRMT1 methylates MyoD. To investigate the occurrence of in vivo methylation of MyoD, we performed metabolical labeling of HEK293T cells with L-[methy-3H]-methionine. Cells were transfected with Flag-tagged MyoD in the absence and presence of AdOx and simultaneously metabolical labeling was performed for 1h in the presence of translational inhibitors. Flag-MyoD protein was immunopurified from the cell extracts, resolved by SDS-PAGE and methylation was detected by autoradiography. The data indicate that in vivo methylation of MyoD occurs and was inhibited in the presence of AdOx. In order to map the methylation site(s) in MyoD, we expressed several N-and C-terminal deletion constructs of MyoD as GST-tagged fusions in bacteria. In vitro methylation in the presence of GST-PRMT1 revealed that the methylation site(s) of PRMT1 in MyoD are located between amino acid 102 and 318, and which encompass the bHLH domain and the C-terminal domain.
To identify the exact site(s) of PRMT1 methylation in MyoD we methylated MyoD in the presence of GST-PRMT1 in vitro. The ESI mass spectrum revealed a doubly charged peak at m/z 910.36 corresponding to the dimethylated sequence of the tryptic MyoD fragment RQNGYDTAYYSEAVR (amino acids 221-235). Fragment ion (MS/MS) spectrum resulting from this doubly charged precursor clearly indicated that the first arginine within the peptide (R221 in the full-length context of MyoD) is dimethylated.
In conclusion, PRMTs play an positive role in regulating the low serum medium induced C2C12 cells differentiation. Histone arginine methylation by PRMTs along with other histone modifications and the activation of transcription factors that jointly exert an increased expression of myogenin gene and result in the C2C12 cells to differentiation. We found for the first time that PRMT1 methylate MyoD in vitro and in vivo. Further studies on the regulatory functions of PRMT1 in C2C12 cell differentiation shed lights on our understanding of muscle differentiation.
MyoD是碱性螺旋-环-螺旋(basic helix-loop-helix, bHLH)家族的一个重要蛋白,在肌肉分化过程中起关键作用。我们以低血清诱导小鼠C2C12细胞作为肌肉分化的模型,并对其分化机制以及分化过程中早期分化标志—myogenin基因启动子区转录相关因子的结合进行研究,特别是精氨酸甲基转移酶修饰对myogenin基因表达调控机制。
C2C12细胞,主要呈三角形和纺锤形,少数多边形；而低血清诱导处理后,C2C12细胞逐渐呈现典型的分化形态,如胞体伸长,出现多核肌纤维类似结构并整齐排列等。我们利用甲基转移酶抑制剂AdOx处理C2C12细胞后发现,C2C12细胞的分化受到抑制。包括细胞形态学上不能出现多核肌纤维类似结构,分化标志myogenin的蛋白水平及mRNA水平的抑制。而组蛋白修饰酶PRMT1、PCAF及CARM1的蛋白质水平在药物处理前后变化不明显。表明甲基化修饰可能是肌肉分化过程中的必需过程。
双荧光素酶报告基因分析发现,在转染的各PRMT家族成员中,PRMT1和CARM1显著地增强myogenin基因启动子活性。我们进一步共转染组蛋白乙酰基转移酶PCAF、当PRMT1与CARM1及PCAF共转染时,比单独转染三者任何一个,或二二组合,激活效应更明显。说明PRMT1可与CARM1及PCAF协同激活MyoD介导的myogenin基因启动子活性。PRMT1是肌肉分化主导开关(master switch) MyoD的转录共激活子。
染色质免疫沉淀(Chromatin Immunoprecipitation, ChIP)分析是近些年发展起来检测蛋白因子在体内与染色质的结合,进而为蛋白因子参与染色质水平基因转录调控提供证据的方法。本研究运用该方法,检测了低血清诱导的C2C12细胞分化过程中,肌细胞分化决定因子MyoD、乙酰转移酶PCAF与精氨酸甲基转移酶CARM1及PRMT1在myogenin基因启动子区染色质的结合情况。这些转录因子在诱导3h后即可结合到染色质。
GST-pulldown实验显示,MyoD与PRMT1共存于一个复合物中。我们进一步确定了MyoD的氨基端及bHLH结构域与PRMT1相互作用,而MyoD的羧基端(MyoD162-318)则不能与PRMT1相互作用。将MyoD亚克隆至pEGFP-C1表达绿色荧光蛋白标签的融合蛋白,将PRMT1克隆至pmCherry-C1载体表达带红色荧光蛋白标签的融合蛋白。将GFP融合的MyoD与Cherry融合的PRMT1共转染C2C12细胞,48h后用激光扫描共聚焦荧光显微镜观察。我们发现,GFP-MyoD主要定位于核内,而Cherry-PRMT1则在整个细胞广泛分布,将二者荧光融合(merge)发现,绿色荧光的MyoD与红色荧光的PRMT1在细胞核内很好的融合为黄色,说明二者在细胞核内定位于相同位置。
我们通过体外GST-pulldown实验以及体内免疫共沉淀(CoIP)实验证实CARM1和PCAF共存于一个复合物中,并且这种相互作用不受AdOx抑制剂的影响的。通过分子生物学手段,我们进一步找到两者的具体结合部位。其中CARM1的催化结构域及C端结构域可与PCAF相互作用,而PCAF主要是通过HAT结构域(PCAF352-658)与CARM1相互作用。
利用体外甲基化反应体系及放射性自显影技术,我们首次发现PRMT家族酶的各个成员,只有PRMT1可甲基化修饰MyoD的精氨酸残基。为了确定MyoD甲基化修饰在细胞内是不是也发生,我们将带Flag标签的MyoD转染HEK 293T细胞,标记3H-甲硫氨酸(3H-Met)的同时加入蛋白质合成抑制剂。免疫亲和沉淀Flag-MyoD,放射自显影。结果显示,MyoD在细胞内存在甲基化修饰,并且AdOx可以抑制MyoD的甲基化修饰。为了确定MyoD的甲基化修饰位点,我们在细菌中表达并纯化了MyoD的N端及C端的删切突变体,加入GST-PRMT1后进行体外甲基化反应并放射性自显影,结果显示MyoD的甲基化修饰位点位于氨基酸162-318之间,即bHLH及C端结构域。
为了确定MyoD甲基化修饰的精确位点,我们在体外用PRMT1甲基化修饰MyoD,ESI质谱鉴定得到带两个电荷且质荷比为910.36的MyoD片段,即RQNGYDTAYYSEAVR(氨基酸221-235),二级质谱鉴定得到上述片段的第一个精氨酸(全长MyoD的221位精氨酸)存在双甲基化修饰。
综上结果,我们认为PRMT1对C2C12细胞的诱导分化过程中具有正调节作用。通过该类酶促的蛋白质精氨酸甲基化,以及其他调节因子对组蛋白的修饰或转录因子的活化,可有效地促进myogenin基因表达,并导致C2C12细胞的分化。我们首次发现PRMT1可甲基化修饰MyoD的精氨酸残基,深入研究PRMT1的调控机制有助于对肌肉细胞诱导分化机制的理解。
Epigenetics is the study of stable alternation in gene expression and function without changing DNA sequence and leading to inheritable phenotype, mainly including DNA methylation, histone modification, chromatin remodeling and non-coding RNA-mediated regulation. Histone modifications including histone methylation, acetylation, phosphorylation and ubiquitination play crucial roles in gene activation and inactivation.
MyoD, one of bHLH protein, play a crucial role in muscle differentiation. In our experiments, Low serum medium was used to induce C2C12 cells to differentiate, and the differentiation mechanism and the binding of associated transcription factors and chromatin modifying enzymes, especially protein arginine methyltransferase 1 to the myogenin promoter were investigated.
The morphology of C2C12 cells are triangular or spindly, and fewer are polygonal. After transferred to low serum medium, the C2C12 cells align regularly and acquire typical myogenic modality gradually, such as a more elongated shape, and multinucleated myofiber-like structure. when the C2C12 cells are treated with adenosine dialdehyde (AdOx) to block the PRMT, Low serum medium induced C2C12 cells differentiation was inhibit. The morphology of C2C12 cells are more big and don't present a multinucleated myofiber-like structure. Moreover, the increase of protein level and mRNA of myogenin was prevented by AdOx during C2C12 cells differentiation. In contrast, the protein level of PRMT1, PCAF and CARM1 was not changed during C2C12 cells differentiation in the presence of AdOx. These data indicate that arginie methylation is involved in muscle differentiation.
Dual-luciferase reporter assay showed that PRMT1 and CARM1 can enhanced the myogenin gene reporter activity when we transfected the C2C12 cells with each member of PRMTs. We further co-transfected C2C12 cells with PRMT1, CARM1 and PCAF, the myogenin gene reporter activity assays showed that PRMT1 synergistically coactivates together with CARM1 and PCAF MyoD-mediated transcription at the myogenin promoter.
Chromatin Immunoprecipitation (ChIP) assay was developed in recent years to detect protein factors that bind to chromatin. The binding of MyoD, PRMT1, PCAF and CARM1 to the myogenin promoter in control or differentiated C2C12 cells induced by low serum medium was studied by this method. We found that these factors were recruited on the myogenin gene promoter after induced for 3 hours in the low serum medium.
In vitro GST-pulldown assays showed that MyoD and PRMT1 exist in a complex, And the binding domain required for the interaction between MyoD and PRMT1 was determined, while the C-terminal domain of MyoD don't interact with PRMTl. We further subcloned MyoD into pEGFP-C1 and PRMT1 into pmCherry-C1, which express GFP-MyoD and Cherry-PRMT1 respectively. When C2C12 were co-transfected with these fusion protein plasmids, MyoD and PRMT1 were visualized by autofluorescence (green) of GFP and (red) of Cherry with a confocal microscopy, respectively. Green fluorescence of GFP-MyoD and red fluorescence of Cherry-PRMT1 merge well (yellow) in nucleus.
To demonstrate the direct interaction between CARM1 with PCAF, the in vitro and in vivo binding assays were done. And the binding domain required for the interaction between CARM1 and PCAF was determined. C-terminal domain of CARM1 (CARM11-141) can not interacts with PCAF, and PCAF HAT (histone acetyltransferase) domain interacts with CARM1.
In vitro methylation reaction assay and autoradiography indicated that, among the members of protein arginine methyltransferase family, only PRMT1 methylates MyoD. To investigate the occurrence of in vivo methylation of MyoD, we performed metabolical labeling of HEK293T cells with L-[methy-3H]-methionine. Cells were transfected with Flag-tagged MyoD in the absence and presence of AdOx and simultaneously metabolical labeling was performed for 1h in the presence of translational inhibitors. Flag-MyoD protein was immunopurified from the cell extracts, resolved by SDS-PAGE and methylation was detected by autoradiography. The data indicate that in vivo methylation of MyoD occurs and was inhibited in the presence of AdOx. In order to map the methylation site(s) in MyoD, we expressed several N-and C-terminal deletion constructs of MyoD as GST-tagged fusions in bacteria. In vitro methylation in the presence of GST-PRMT1 revealed that the methylation site(s) of PRMT1 in MyoD are located between amino acid 102 and 318, and which encompass the bHLH domain and the C-terminal domain.
To identify the exact site(s) of PRMT1 methylation in MyoD we methylated MyoD in the presence of GST-PRMT1 in vitro. The ESI mass spectrum revealed a doubly charged peak at m/z 910.36 corresponding to the dimethylated sequence of the tryptic MyoD fragment RQNGYDTAYYSEAVR (amino acids 221-235). Fragment ion (MS/MS) spectrum resulting from this doubly charged precursor clearly indicated that the first arginine within the peptide (R221 in the full-length context of MyoD) is dimethylated.
In conclusion, PRMTs play an positive role in regulating the low serum medium induced C2C12 cells differentiation. Histone arginine methylation by PRMTs along with other histone modifications and the activation of transcription factors that jointly exert an increased expression of myogenin gene and result in the C2C12 cells to differentiation. We found for the first time that PRMT1 methylate MyoD in vitro and in vivo. Further studies on the regulatory functions of PRMT1 in C2C12 cell differentiation shed lights on our understanding of muscle differentiation.
引文
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