单核苷酸多态性和miRNA对CARM1基因表达的调控机制及其在冠心病中的作用研究
摘要
目的：
阐明调控辅激活因子相关的精氨酸甲基转移酶1(coactivator-associated arginine methyl-transferase1, CARM1)基因表达的分子机制,探索其通过何种作用方式参与冠心病的发生,试图揭示该基因在冠心病发生中的作用及机制,为冠心病的预防和治疗提供新的靶点。
方法：
1)利用real-time PCR和Western blot方法分别在mRNA和蛋白水平上检测冠心病病例和对照的外周血单个核细胞(PBMCs)中CARM1的表达水平；2)综合利用HapMap数据库中连锁不平衡(LD)分析和“DNA元件百科全书”(ENCODE)的功能注释数据,筛选CARM1基因上下游10kb内位于不同LD区域中的潜在功能性单核苷酸多态性(SNP)；在234例健康个体的PBMCs样本中检测CARM1mRNA的表达水平,分析其与SNP基因型的关系；对影响CARM1表达的SNP进行生物学功能研究：应用双荧光素酶报告基因系统检测等位基因特异性的转录激活活性,利用电泳迁移率变更实验(EMSA)、多种转录因子冷竞争实验(MC-EMSA)、电泳超迁移率变更分析(supershift-EMSA)和染色质免疫沉淀(ChIP)分别在体外和细胞内筛选、鉴定等位基因特异性结合的转录因子；3)通过生物信息学预测调控CARM1的靶miRNA;利用real-time PCR检测其在冠心病病例和对照中的表达；通过共转染野生型或种子区突变的CARM13'-UTR区报告基因及靶miRNA模拟物(mimics)证明该miRNA结合CARM13'-UTR种子区；在细胞水平上过表达或敲减该miRNA,通过real-time PCR和Western blot检测CARM1的mRNA和蛋白水平,明确其对CARM1表达的调控；4)通过CARM1的功能性多态位点与血浆同型半胱氨酸(homocysteine, Hey)水平的关联研究,及细胞中过表达人源CARM1后ELISA检测细胞上清及胞内Hcy的水平,探索CARM1对Hcy的调控作用；5)在1010例冠心病病例和3998例对照中进行CARM1的功能性位点与冠心病的关联研究,使用加性模型分析少见等位基因对冠心病发生的效应。
结果：
1)与对照组相比,急性冠脉综合征(ACS)组PBMCs中CARM1的mRNA水平升高3.9倍,蛋白水平升高1.5倍；2)根据LD分析和ENCODE证据,筛选出4个潜在功能性SNP；在健康人群中3个SNP位点与CARM1的表达水平相关,即rsl2460421(A/G)、rsl17569851(T/C)和rs4804544(A/G),其中后两个位点完全连锁；报告基因实验结果表明,rsl2460421-rsl17569851单体型GC和单体型AT的转录活性分别是单体型GT的2.0倍和1.7倍；EMSA结果显示rs12460421的A等位基因与核蛋白的结合能力强于G,rsl17569851的C等位基因与核蛋白的结合能力强于T;MC-EMSA筛选出转录因子Egr-1与这两个位点结合；supershift-EMSA和ChIP实验分别在体外和细胞内水平证明Egr-1结合这两个位点且不同等位基因与Egr-1的亲和力不同；3)生物信息学预测与CARM1结合的靶miRNA为miR-15a和miR-16；与对照组相比,ACS病例组的PBMCs中1miR-15a的表达水平降低37%,而miR-16则表达升高；野生型和突变型CARM13'-UTR的报告基因与miR-15a mimic共转染细胞后,双荧光素酶报告基因检测结果显示miR-15a与CARM13'-UTR的两个种子区都发生结合；在293T细胞中过表达miR-15a不引起CARM1下调,但敲减]miR-15a后CARM1表达增加；4)在健康人群中,CARM1的功能性多态位点rs117569851与血浆Hcy水平存在关联(P=0.02),每增加一个少见等位基因T,Hcy的水平降低2.16μmol/L;5)rsl17569851与冠心病的关联研究未检出统计学差异(校正年龄、性别、BMI后P=-0.053)。
结论：
1)ACS患者PBMCs中CARM1基因的1mRNA和蛋白水平表达水平升高,提示该基因在冠心病的发生中可能起重要作用；
2) CARM1启动子区功能性多态位点rs117569851的少见等位基因T通过降低与转录因子Egr-1的结合,下调CARM1的表达,降低血浆Hcy水平,从而可能潜在减少冠心病的发病风险；
3) miR-15a在ACS患者PBMCs中表达下降,减轻了对CARM1mRNA的降解和蛋白翻译的抑制作用,从而使CARM1的表达水平升高；
4)关联研究表明CARM1的功能性多态rs117569851通过调控Hcy代谢,可能参与冠心病的发生。
目的：
GWAS表明位于脂蛋白脂肪酶(lipoprotein lipase, LPL)3'-UTR的多态位点rs1059611与血脂水平关联,但其是否具有生物学功能尚不清楚。本研究初步探索该位点对转录活性及转录因子亲和力的影响。
方法：
1)在pGL-3promoter载体的报告基因下游插入含有rs1059611(C/T)位点的基因组序列,构建重组质粒；利用双荧光素酶报告基因系统,检测该位点对转录活性的影响；
2)提取人内脏脂肪组织核蛋白,与含有rs1059611(C/T)位点的探针孵育后进行电泳迁移率变更实验(EMSA),比较两个等位基因与核蛋白结合形成的迁移带的差异；分别用C等位基因和T等位基因的冷竞争探针与核蛋白预孵育,再加入生物素标记的探针进行冷竞争EMSA实验,观察迁移带是否消失。
结果：
1)含有rs1059611位点的序列能够增强转录活性,常见等位基因T转换为少见等位基因C后转录活性显著增高(0.69vs1.00)；2)rs1059611的T等位基因探针与脂肪组织核蛋白结合形成的迁移带在灰度上高于C等位基因;个体A的脂肪组织核蛋白与等位基因结合的差异比个体B更显著;200倍冷竞争探针预孵育使迁移带完全消失。
结论：
rs1059611的常见等位基因T转换为少见等位基因C后转录活性增高;rs1059611的常见等位基因T结合转录因子的亲和力大于少见等位基因C。说明rs1059611具有影响转录活性的生物学功能。
Objective:
The study was designed to clarify the molecular regulation mechanism of coactivator-associated arginine methyltransferase1(CARM1) expression and explore its function in coronary artery disease (CAD). The attempt to uncover the function and mechanism of CARM1gene might provide a new target of prevention and treatment of CAD.
Methods:
1) The mRNA and protein expression levels of CARM1in PBMCs between CAD and control groups were detected with real-time PCR and Western blot;2) The potential functional SNPs in different linkage disequilibrium (LD) blocks were screened by integrating evidence of both HapMap project database and Encyclopedia Of DNA Elements (ENCODE) functional database; the relationship between these SNPs and CARM1mRNA expression levels in234healthy subjects was analyzed; the biological functional studies of the SNPs related with CARM1expression were conducted as follows:dual luciferase reporter activity assay to detect allele specific transcriptional activation activity; electrophoretic mobility shift assay (EMSA), multiplexed competitors EMSA (MC-EMSA), supershift-EMSA and ChIP to screen and determine the transcription factors specifically binding to different alleles, respectively in vitro and in vivo;3) Based on bioinformatics prediction of target miRNAs of CARM1, the miRNA expression level was detected in CAD cases and controls with real-time PCR; co-transfection of luciferase reporter gene containing CARM13'-UTR with or without seed mutations and miRNA mimics was performed to determine the binding of miRNA to CARM13'-UTR; the regulation of mRNA and protein expression level of CARM1with overexpression or knockdown of miRNA was detected;4) To explore the regulation of homocysteine (Hcy) by CARM1, we conducted the association study of the functional variant in CARM1with plasma Hcy levels and measured the concentration of Hcy in cell supernatants and lysates with ELISA after overexpression human CARM1plasmid;5) Association study of the functional variant in CARM1with CAD in1010cases and3998controls was conducted, and the effect of the minor allele on CAD risk was examined in an additive genetic model.
Results:
1) Compared with the control group, the mRNA and protein expression level of CARM1in PBMCs of acute coronary syndrome (ACS) group increased3.9fold and1.5fold, respectively;2) We seletcted4potential functional variants based on the evidence of LD analysis and ENCODE database,3of which were related with CARM1expression levels in healthy population. These3SNPs were rs12460421(A/G), rs117569851(T/C) and rs4804544(A/G), and the last two SNPs were completely linkage disequilibrium. The luciferase reporter activity assay showed that the transcriptional activity of rs12460421-rs117569851haplotype GC and AT was2.0fold and1.7fold of that of haplotype GT, repectively; EMS A demonstrated that A allele of rs12460421had greater binding affinity of nuclear protein than G allele, and C allele of rs117569851had greater binding affinity of nuclear protein than T allele; MC-EMSA showed that Egr-1might bind to both of the SNPs; supershift-EMSA and ChIP assay certified the identification of Egr-1binding to the two SNPs with allele specific binding affinity;3) miR-15a and miR-16was predicted to target CARM1using bioinformatics method; miR-15a expression level in PBMCs was decreased by37%in ACS cases compared with controls, while miR-16was upregulated in ACS cases; after co-transfected of luciferase reporter gene containing CARM13'-UTR with or without seed mutations and miR-15a mimics, the results of dual luciferase reporter assay system showed that miR-15a binded to both of the seeds of miRNA binding sites in CARM13'-UTR; CARM1expression was upregulated by the knockdown of miR-15a, however it was not downregulated by the overexpression of miR-15a;4) The functional variant rs117569851in CARM1was associated with plasma Hcy levels in a healthy population involving406subjects (P=0.02), and the Hcy levels decreased2.16μmol/L per minor allele T;5) Genetic analysis did not find the association of rs117569851with CAD (P=0.053, adjusted by age, sex and BMI).
Conclusions:
1) The mRNA and protein expression of CARM1in ACS patients increased compared with controls, which indicated that CARM1might play a role in CAD pathogenesis;
2) The minor allele T of rs117569851locating in CARM1promoter downregulated the expression level of CARM1gene through lower binding affinity of transcription factor Egr-1, decreased the plasma Hcy level, and potentially reduced the risk of CAD;
3) The decreased expression of miR-15a in PBMCs of CAD patients might reduce the inhibition effect on mRNA degradation and protein translation of CARM1, inducing CARM1expression upregulated;
4) Association studies showed that CARM1might play a role in CAD pathogenesis through regulating Hcy metabolism.
Objective
rsl059611, located in3'-UTR of LPL, is associated with plasma lipid concentrations in GWAS, but its biological function is unclear. The study is designed for tentative exploration of its effect on transcriptional activity and transcription factor affinity.
Methods
1) The genomic sequence containing rs1059611was inserted into the downstream of the reporter gene in pGL-3promoter vector to construct a recombinant plasmid; the effect of rs1059611on transcriptional activity was illustrated with dual-luciferase reporter activity system;2) Incubation with nuclear extract from human visceral adipose tissue and probes containing rsl059611(C/T) sequence, followed by electrophoretic mobility shift assay (EMSA) was conducted to compare the differences of shift bands formed by probes and nuclear protein between two alleles; competitor EMSA was carried out with pre-incubation with competitors of allele C and T with nuclear extract respectively and adding biotin labeled probes later, to observe whether the shift bands vanish.
Results
1) The transcriptional activity was enhanced by sequence containing rsl059611, and increased significantly after major allele T converting to minor allele C (0.69vs.1.00);2) the greyscale of shift bands formed by probes of allele T for rsl059611binding with nuclear extract of adipose tissue was higher than allele C; the discrepancy of shift bands between two alleles with nuclear extract of adipose tissue from individual A was greater than that from individual B; the shift bands were completely abolished by pre-incubation with200fold competitor probes.
Conclusion
The transcriptional activity was increased after major allele T converting to minor allele C; the affinity of major allele T binding to transcription factor was greater than that of minor allele C. It declared that rsl059611might have biological functions of affecting transcriptional activity.
阐明调控辅激活因子相关的精氨酸甲基转移酶1(coactivator-associated arginine methyl-transferase1, CARM1)基因表达的分子机制,探索其通过何种作用方式参与冠心病的发生,试图揭示该基因在冠心病发生中的作用及机制,为冠心病的预防和治疗提供新的靶点。
方法：
1)利用real-time PCR和Western blot方法分别在mRNA和蛋白水平上检测冠心病病例和对照的外周血单个核细胞(PBMCs)中CARM1的表达水平；2)综合利用HapMap数据库中连锁不平衡(LD)分析和“DNA元件百科全书”(ENCODE)的功能注释数据,筛选CARM1基因上下游10kb内位于不同LD区域中的潜在功能性单核苷酸多态性(SNP)；在234例健康个体的PBMCs样本中检测CARM1mRNA的表达水平,分析其与SNP基因型的关系；对影响CARM1表达的SNP进行生物学功能研究：应用双荧光素酶报告基因系统检测等位基因特异性的转录激活活性,利用电泳迁移率变更实验(EMSA)、多种转录因子冷竞争实验(MC-EMSA)、电泳超迁移率变更分析(supershift-EMSA)和染色质免疫沉淀(ChIP)分别在体外和细胞内筛选、鉴定等位基因特异性结合的转录因子；3)通过生物信息学预测调控CARM1的靶miRNA;利用real-time PCR检测其在冠心病病例和对照中的表达；通过共转染野生型或种子区突变的CARM13'-UTR区报告基因及靶miRNA模拟物(mimics)证明该miRNA结合CARM13'-UTR种子区；在细胞水平上过表达或敲减该miRNA,通过real-time PCR和Western blot检测CARM1的mRNA和蛋白水平,明确其对CARM1表达的调控；4)通过CARM1的功能性多态位点与血浆同型半胱氨酸(homocysteine, Hey)水平的关联研究,及细胞中过表达人源CARM1后ELISA检测细胞上清及胞内Hcy的水平,探索CARM1对Hcy的调控作用；5)在1010例冠心病病例和3998例对照中进行CARM1的功能性位点与冠心病的关联研究,使用加性模型分析少见等位基因对冠心病发生的效应。
结果：
1)与对照组相比,急性冠脉综合征(ACS)组PBMCs中CARM1的mRNA水平升高3.9倍,蛋白水平升高1.5倍；2)根据LD分析和ENCODE证据,筛选出4个潜在功能性SNP；在健康人群中3个SNP位点与CARM1的表达水平相关,即rsl2460421(A/G)、rsl17569851(T/C)和rs4804544(A/G),其中后两个位点完全连锁；报告基因实验结果表明,rsl2460421-rsl17569851单体型GC和单体型AT的转录活性分别是单体型GT的2.0倍和1.7倍；EMSA结果显示rs12460421的A等位基因与核蛋白的结合能力强于G,rsl17569851的C等位基因与核蛋白的结合能力强于T;MC-EMSA筛选出转录因子Egr-1与这两个位点结合；supershift-EMSA和ChIP实验分别在体外和细胞内水平证明Egr-1结合这两个位点且不同等位基因与Egr-1的亲和力不同；3)生物信息学预测与CARM1结合的靶miRNA为miR-15a和miR-16；与对照组相比,ACS病例组的PBMCs中1miR-15a的表达水平降低37%,而miR-16则表达升高；野生型和突变型CARM13'-UTR的报告基因与miR-15a mimic共转染细胞后,双荧光素酶报告基因检测结果显示miR-15a与CARM13'-UTR的两个种子区都发生结合；在293T细胞中过表达miR-15a不引起CARM1下调,但敲减]miR-15a后CARM1表达增加；4)在健康人群中,CARM1的功能性多态位点rs117569851与血浆Hcy水平存在关联(P=0.02),每增加一个少见等位基因T,Hcy的水平降低2.16μmol/L;5)rsl17569851与冠心病的关联研究未检出统计学差异(校正年龄、性别、BMI后P=-0.053)。
结论：
1)ACS患者PBMCs中CARM1基因的1mRNA和蛋白水平表达水平升高,提示该基因在冠心病的发生中可能起重要作用；
2) CARM1启动子区功能性多态位点rs117569851的少见等位基因T通过降低与转录因子Egr-1的结合,下调CARM1的表达,降低血浆Hcy水平,从而可能潜在减少冠心病的发病风险；
3) miR-15a在ACS患者PBMCs中表达下降,减轻了对CARM1mRNA的降解和蛋白翻译的抑制作用,从而使CARM1的表达水平升高；
4)关联研究表明CARM1的功能性多态rs117569851通过调控Hcy代谢,可能参与冠心病的发生。
目的：
GWAS表明位于脂蛋白脂肪酶(lipoprotein lipase, LPL)3'-UTR的多态位点rs1059611与血脂水平关联,但其是否具有生物学功能尚不清楚。本研究初步探索该位点对转录活性及转录因子亲和力的影响。
方法：
1)在pGL-3promoter载体的报告基因下游插入含有rs1059611(C/T)位点的基因组序列,构建重组质粒；利用双荧光素酶报告基因系统,检测该位点对转录活性的影响；
2)提取人内脏脂肪组织核蛋白,与含有rs1059611(C/T)位点的探针孵育后进行电泳迁移率变更实验(EMSA),比较两个等位基因与核蛋白结合形成的迁移带的差异；分别用C等位基因和T等位基因的冷竞争探针与核蛋白预孵育,再加入生物素标记的探针进行冷竞争EMSA实验,观察迁移带是否消失。
结果：
1)含有rs1059611位点的序列能够增强转录活性,常见等位基因T转换为少见等位基因C后转录活性显著增高(0.69vs1.00)；2)rs1059611的T等位基因探针与脂肪组织核蛋白结合形成的迁移带在灰度上高于C等位基因;个体A的脂肪组织核蛋白与等位基因结合的差异比个体B更显著;200倍冷竞争探针预孵育使迁移带完全消失。
结论：
rs1059611的常见等位基因T转换为少见等位基因C后转录活性增高;rs1059611的常见等位基因T结合转录因子的亲和力大于少见等位基因C。说明rs1059611具有影响转录活性的生物学功能。
Objective:
The study was designed to clarify the molecular regulation mechanism of coactivator-associated arginine methyltransferase1(CARM1) expression and explore its function in coronary artery disease (CAD). The attempt to uncover the function and mechanism of CARM1gene might provide a new target of prevention and treatment of CAD.
Methods:
1) The mRNA and protein expression levels of CARM1in PBMCs between CAD and control groups were detected with real-time PCR and Western blot;2) The potential functional SNPs in different linkage disequilibrium (LD) blocks were screened by integrating evidence of both HapMap project database and Encyclopedia Of DNA Elements (ENCODE) functional database; the relationship between these SNPs and CARM1mRNA expression levels in234healthy subjects was analyzed; the biological functional studies of the SNPs related with CARM1expression were conducted as follows:dual luciferase reporter activity assay to detect allele specific transcriptional activation activity; electrophoretic mobility shift assay (EMSA), multiplexed competitors EMSA (MC-EMSA), supershift-EMSA and ChIP to screen and determine the transcription factors specifically binding to different alleles, respectively in vitro and in vivo;3) Based on bioinformatics prediction of target miRNAs of CARM1, the miRNA expression level was detected in CAD cases and controls with real-time PCR; co-transfection of luciferase reporter gene containing CARM13'-UTR with or without seed mutations and miRNA mimics was performed to determine the binding of miRNA to CARM13'-UTR; the regulation of mRNA and protein expression level of CARM1with overexpression or knockdown of miRNA was detected;4) To explore the regulation of homocysteine (Hcy) by CARM1, we conducted the association study of the functional variant in CARM1with plasma Hcy levels and measured the concentration of Hcy in cell supernatants and lysates with ELISA after overexpression human CARM1plasmid;5) Association study of the functional variant in CARM1with CAD in1010cases and3998controls was conducted, and the effect of the minor allele on CAD risk was examined in an additive genetic model.
Results:
1) Compared with the control group, the mRNA and protein expression level of CARM1in PBMCs of acute coronary syndrome (ACS) group increased3.9fold and1.5fold, respectively;2) We seletcted4potential functional variants based on the evidence of LD analysis and ENCODE database,3of which were related with CARM1expression levels in healthy population. These3SNPs were rs12460421(A/G), rs117569851(T/C) and rs4804544(A/G), and the last two SNPs were completely linkage disequilibrium. The luciferase reporter activity assay showed that the transcriptional activity of rs12460421-rs117569851haplotype GC and AT was2.0fold and1.7fold of that of haplotype GT, repectively; EMS A demonstrated that A allele of rs12460421had greater binding affinity of nuclear protein than G allele, and C allele of rs117569851had greater binding affinity of nuclear protein than T allele; MC-EMSA showed that Egr-1might bind to both of the SNPs; supershift-EMSA and ChIP assay certified the identification of Egr-1binding to the two SNPs with allele specific binding affinity;3) miR-15a and miR-16was predicted to target CARM1using bioinformatics method; miR-15a expression level in PBMCs was decreased by37%in ACS cases compared with controls, while miR-16was upregulated in ACS cases; after co-transfected of luciferase reporter gene containing CARM13'-UTR with or without seed mutations and miR-15a mimics, the results of dual luciferase reporter assay system showed that miR-15a binded to both of the seeds of miRNA binding sites in CARM13'-UTR; CARM1expression was upregulated by the knockdown of miR-15a, however it was not downregulated by the overexpression of miR-15a;4) The functional variant rs117569851in CARM1was associated with plasma Hcy levels in a healthy population involving406subjects (P=0.02), and the Hcy levels decreased2.16μmol/L per minor allele T;5) Genetic analysis did not find the association of rs117569851with CAD (P=0.053, adjusted by age, sex and BMI).
Conclusions:
1) The mRNA and protein expression of CARM1in ACS patients increased compared with controls, which indicated that CARM1might play a role in CAD pathogenesis;
2) The minor allele T of rs117569851locating in CARM1promoter downregulated the expression level of CARM1gene through lower binding affinity of transcription factor Egr-1, decreased the plasma Hcy level, and potentially reduced the risk of CAD;
3) The decreased expression of miR-15a in PBMCs of CAD patients might reduce the inhibition effect on mRNA degradation and protein translation of CARM1, inducing CARM1expression upregulated;
4) Association studies showed that CARM1might play a role in CAD pathogenesis through regulating Hcy metabolism.
Objective
rsl059611, located in3'-UTR of LPL, is associated with plasma lipid concentrations in GWAS, but its biological function is unclear. The study is designed for tentative exploration of its effect on transcriptional activity and transcription factor affinity.
Methods
1) The genomic sequence containing rs1059611was inserted into the downstream of the reporter gene in pGL-3promoter vector to construct a recombinant plasmid; the effect of rs1059611on transcriptional activity was illustrated with dual-luciferase reporter activity system;2) Incubation with nuclear extract from human visceral adipose tissue and probes containing rsl059611(C/T) sequence, followed by electrophoretic mobility shift assay (EMSA) was conducted to compare the differences of shift bands formed by probes and nuclear protein between two alleles; competitor EMSA was carried out with pre-incubation with competitors of allele C and T with nuclear extract respectively and adding biotin labeled probes later, to observe whether the shift bands vanish.
Results
1) The transcriptional activity was enhanced by sequence containing rsl059611, and increased significantly after major allele T converting to minor allele C (0.69vs.1.00);2) the greyscale of shift bands formed by probes of allele T for rsl059611binding with nuclear extract of adipose tissue was higher than allele C; the discrepancy of shift bands between two alleles with nuclear extract of adipose tissue from individual A was greater than that from individual B; the shift bands were completely abolished by pre-incubation with200fold competitor probes.
Conclusion
The transcriptional activity was increased after major allele T converting to minor allele C; the affinity of major allele T binding to transcription factor was greater than that of minor allele C. It declared that rsl059611might have biological functions of affecting transcriptional activity.
引文
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[1]Tsoi LC, Spain SL, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity[J]. Nat Genet.2012;44(12):1341-1348.
[2]Kathiresan S, Voight BF, et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants[J]. Nat Genet.2009;41(3):334-341.
[3]Hinohara K, Nakajima T, et al. Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations[J]. J Hum Genet.2008;53(4):357-359.
[4]Teslovich TM, Musunuru K, et al. Biological, clinical and population relevance of 95 loci for blood lipids[J]. Nature.2010;466(7307):707-713.
[5]Teyssier C, Chen D, et al. Requirement for multiple domains of the protein arginine methyltransferase CARM1 in its transcriptional coactivator function[J]. J Biol Chem.2002;277(48):46066-46072.
[6]Teyssier C, Ou CY, et al. Transcriptional intermediary factor 1 alpha mediates physical interaction and functional synergy between the coactivator-associated arginine methyltransferase 1 and glucocorticoid receptor-interacting protein 1 nuclear receptor coactivators[J]. Mol Endocrinol.2006;20(6):1276-1286.
[7]Troffer-Charlier N, Cura V, et al. Functional insights from structures of coactivator-associated arginine methyltransferase 1 domains[J]. EMBO J.2007; 26(20):4391-4401.
[8]Warfel NA, Newton AC. Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP):a new player in cell signaling[J]. J Biol Chem. 2012;287(6):3610-3616.
[9]Fan S, Ma YX, et al. The multisubstrate adapter Gabl regulates hepatocyte growth factor (scatter factor)-c-Met signaling for cell survival and DNArepair[J]. Mol Cell Biol.2001;21(15):4968-4984.
[101 Yue WW, Hassler M, et al. Insights into histone code syntax from structural and biochemical studies of CARM1 methyltransferase[J]. EMBO J.2007;26 (20): 4402-4412.
[11]Mudd SH, Cantoni GL. Activation of methionine for transmethylation. Ⅲ. The methionine-activating enzyme of Bakers' yeast[J]. J Biol Chem.1958;231 (1): 481-492.
[12]Mato JM, Alvarez L, et al. S-adenosylmethionine synthesis:molecular mechanisms and clinical implications [J]. Pharmacol Ther.1997;73(3):265-280.
(13] Kullo IJ, Ding K, et al. Novel genomic loci influencing plasma homocysteine levels[J]. Stroke.2006;37(7):1703-1709.
[14]Schurter BT, Koh SS, et al. Methylation of histone H3 by coactivator-associated arginine methyltransferase 1[J]. Biochemistry.2001;40(19):5747-5756.
[15]Chen D, Huang SM, et al. Synergistic, p160 coactivator-dependent enhancement of estrogen receptor function by CARM1 and p300[J]. J Biol Chem.2000;275 (52):40810-40816.
[16]An W, Kim J, et al. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53[J]. Cell.2004;117(6):735-748.
[17]Covic M, Hassa PO, et al. Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-kappaB-dependent gene expression[J]. EMBO J.2005;24(1):85-96.
[18]Wei Y, Horng JC, et al. Contribution to stability and folding of a buried polar residue at the CARM1 methylation site of the KIX domain of CBP[J]. Biochemistry.2003;42(23):7044-7049.
[19]Naeem H, Cheng D, et al. The activity and stability of the transcriptional coactivator p/CIP/SRC-3 are regulated by CARM1-dependent methylation[J]. Mol Cell Biol.2007;27(1):120-134.
[20]Lee J, Bedford MT. PABP1 identified as an arginine methyltransferase substrate using high-density protein arrays[J]. EMBO Rep.2002;3(3):268-273.
[21]Fujiwara T, Mori Y, et al. CARM1 regulates proliferation of PC12 cells by methylating HuD[J]. Mol Cell Biol.2006;26(6):2273-2285.
[22]Li H, Park S, et al. Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. Coactivator-associated arginine methyltransferase[J]. J Biol Chem.2002;277(47):44623-44630.
[23]Ohkura N, Takahashi M, et al. Coactivator-associated arginine methyltransferase 1, CARM1, affects pre-mRNA splicing in an isoform-specific manner [J]. J Biol Chem.2005;280(32):28927-28935.
[24]Cheng D, Cote J, et al. The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing[J]. Mol Cell.2007;25(1):71-83.
[25]Kutuk O, Basaga H. Inflammation meets oxidation:NF-kappaB as a mediator of initial lesion development in atherosclerosis[J]. Trends Mol Med.2003; 9(12): 549-557.
[26]Martin-Ventura JL, Blanco-Colio LM, et al. NF-kappaB activation and Fas ligand overexpression in blood and plaques of patients with carotid atherosclerosis: potential implication in plaque instability [J]. Stroke.2004;35(2):458-463.
[27]Sun X, Feinberg MW. NF-kappaB and hypoxia:a double-edged sword in atherosclerosis[J]. Am J Pathol.2012;181(5):1513-1517.
[28]Hassa PO, Covic M, et al. Protein arginine methyltransferase 1 coactivates NF-kappaB-dependent gene expression synergistically with CARM1 and PARP1[J]. J Mol Biol.2008;377(3):668-678.
[29]Wu Q, Bruce AW, et al. CARM1 is required in embryonic stem cells to maintain pluripotency and resist differentiation[J]. Stem Cells.2009;27(11):2637-2645.
[30]Yadav N, Lee J, et al. Specific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice[J]. Proc Natl Acad Sci U S A.2003; 100(11):6464-6468.
[31]O'Brien KB, Alberich-Jorda M, et al. CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells[J]. Development. 2010;137(13):2147-2156.
[32]Fauquier L, Duboe C, et al. Dual role of the arginine methyltransferase CARM1 in the regulation of c-Fos target genes[J]. FASEB J.2008;22(9):3337-3347.
[33]Yadav N, Cheng D, et al. CARM1 promotes adipocyte differentiation by coactivating PPARgamma[J]. EMBO Rep.2008;9(2):193-198.
[34]Xu Z, Jiang J, et al. MicroRNA-181 regulates CARM1 and histone arginine methylation to promote differentiation of human embryonic stem cells[J]. PLoS One.2013;8(1):e53146.
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[1]Tsoi LC, Spain SL, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity[J]. Nat Genet.2012;44(12):1341-1348.
[2]Kathiresan S, Voight BF, et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants[J]. Nat Genet.2009;41(3):334-341.
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[4]Teslovich TM, Musunuru K, et al. Biological, clinical and population relevance of 95 loci for blood lipids[J]. Nature.2010;466(7307):707-713.
[5]Teyssier C, Chen D, et al. Requirement for multiple domains of the protein arginine methyltransferase CARM1 in its transcriptional coactivator function[J]. J Biol Chem.2002;277(48):46066-46072.
[6]Teyssier C, Ou CY, et al. Transcriptional intermediary factor 1 alpha mediates physical interaction and functional synergy between the coactivator-associated arginine methyltransferase 1 and glucocorticoid receptor-interacting protein 1 nuclear receptor coactivators[J]. Mol Endocrinol.2006;20(6):1276-1286.
[7]Troffer-Charlier N, Cura V, et al. Functional insights from structures of coactivator-associated arginine methyltransferase 1 domains[J]. EMBO J.2007; 26(20):4391-4401.
[8]Warfel NA, Newton AC. Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP):a new player in cell signaling[J]. J Biol Chem. 2012;287(6):3610-3616.
[9]Fan S, Ma YX, et al. The multisubstrate adapter Gabl regulates hepatocyte growth factor (scatter factor)-c-Met signaling for cell survival and DNArepair[J]. Mol Cell Biol.2001;21(15):4968-4984.
[101 Yue WW, Hassler M, et al. Insights into histone code syntax from structural and biochemical studies of CARM1 methyltransferase[J]. EMBO J.2007;26 (20): 4402-4412.
[11]Mudd SH, Cantoni GL. Activation of methionine for transmethylation. Ⅲ. The methionine-activating enzyme of Bakers' yeast[J]. J Biol Chem.1958;231 (1): 481-492.
[12]Mato JM, Alvarez L, et al. S-adenosylmethionine synthesis:molecular mechanisms and clinical implications [J]. Pharmacol Ther.1997;73(3):265-280.
(13] Kullo IJ, Ding K, et al. Novel genomic loci influencing plasma homocysteine levels[J]. Stroke.2006;37(7):1703-1709.
[14]Schurter BT, Koh SS, et al. Methylation of histone H3 by coactivator-associated arginine methyltransferase 1[J]. Biochemistry.2001;40(19):5747-5756.
[15]Chen D, Huang SM, et al. Synergistic, p160 coactivator-dependent enhancement of estrogen receptor function by CARM1 and p300[J]. J Biol Chem.2000;275 (52):40810-40816.
[16]An W, Kim J, et al. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53[J]. Cell.2004;117(6):735-748.
[17]Covic M, Hassa PO, et al. Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-kappaB-dependent gene expression[J]. EMBO J.2005;24(1):85-96.
[18]Wei Y, Horng JC, et al. Contribution to stability and folding of a buried polar residue at the CARM1 methylation site of the KIX domain of CBP[J]. Biochemistry.2003;42(23):7044-7049.
[19]Naeem H, Cheng D, et al. The activity and stability of the transcriptional coactivator p/CIP/SRC-3 are regulated by CARM1-dependent methylation[J]. Mol Cell Biol.2007;27(1):120-134.
[20]Lee J, Bedford MT. PABP1 identified as an arginine methyltransferase substrate using high-density protein arrays[J]. EMBO Rep.2002;3(3):268-273.
[21]Fujiwara T, Mori Y, et al. CARM1 regulates proliferation of PC12 cells by methylating HuD[J]. Mol Cell Biol.2006;26(6):2273-2285.
[22]Li H, Park S, et al. Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. Coactivator-associated arginine methyltransferase[J]. J Biol Chem.2002;277(47):44623-44630.
[23]Ohkura N, Takahashi M, et al. Coactivator-associated arginine methyltransferase 1, CARM1, affects pre-mRNA splicing in an isoform-specific manner [J]. J Biol Chem.2005;280(32):28927-28935.
[24]Cheng D, Cote J, et al. The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing[J]. Mol Cell.2007;25(1):71-83.
[25]Kutuk O, Basaga H. Inflammation meets oxidation:NF-kappaB as a mediator of initial lesion development in atherosclerosis[J]. Trends Mol Med.2003; 9(12): 549-557.
[26]Martin-Ventura JL, Blanco-Colio LM, et al. NF-kappaB activation and Fas ligand overexpression in blood and plaques of patients with carotid atherosclerosis: potential implication in plaque instability [J]. Stroke.2004;35(2):458-463.
[27]Sun X, Feinberg MW. NF-kappaB and hypoxia:a double-edged sword in atherosclerosis[J]. Am J Pathol.2012;181(5):1513-1517.
[28]Hassa PO, Covic M, et al. Protein arginine methyltransferase 1 coactivates NF-kappaB-dependent gene expression synergistically with CARM1 and PARP1[J]. J Mol Biol.2008;377(3):668-678.
[29]Wu Q, Bruce AW, et al. CARM1 is required in embryonic stem cells to maintain pluripotency and resist differentiation[J]. Stem Cells.2009;27(11):2637-2645.
[30]Yadav N, Lee J, et al. Specific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice[J]. Proc Natl Acad Sci U S A.2003; 100(11):6464-6468.
[31]O'Brien KB, Alberich-Jorda M, et al. CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells[J]. Development. 2010;137(13):2147-2156.
[32]Fauquier L, Duboe C, et al. Dual role of the arginine methyltransferase CARM1 in the regulation of c-Fos target genes[J]. FASEB J.2008;22(9):3337-3347.
[33]Yadav N, Cheng D, et al. CARM1 promotes adipocyte differentiation by coactivating PPARgamma[J]. EMBO Rep.2008;9(2):193-198.
[34]Xu Z, Jiang J, et al. MicroRNA-181 regulates CARM1 and histone arginine methylation to promote differentiation of human embryonic stem cells[J]. PLoS One.2013;8(1):e53146.
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