无义突变与“遗传补偿效应”
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摘要
"遗传补偿效应"(genetic compensation response, GCR)是近年来在斑马鱼(Danio rerio)中最先描述的一个遗传现象,是指当敲低某一个基因时有明显的表型,但此基因的敲除遗传突变体由于其他基因的上调反而没有表型。这种基因敲低和敲除表型上的差异并非斑马鱼所独有,在拟南芥(Arabidopsis thaliana)、小鼠(Mus musculus)等模式生物中都观察到此种现象。这种奇怪的现象一直困扰着基因功能研究。2019年4月3日,Nature同时在线发表两篇论文揭示了其中的奥秘,其中一篇来自于本实验室,另一篇来自于德国Stainier实验室。利用斑马鱼或小鼠培养细胞的不同基因的遗传突变体为模型,两个实验室分别证明无义突变与核酸序列同源性是激活遗传补偿效应的两个先决条件;无义mRNA介导的降解途径参与激活遗传补偿效应;同时还观察到补偿基因的高表达与其转录起始位点处的组蛋白H3K4me3修饰相关。本文具体介绍了这两篇研究论文中提出的"遗传补偿效应"分子机制的异同,以期为克服遗传补偿效应给基因功能研究带来的障碍提供新的思路和方法。
The genetic compensation response(GCR) was firstly described in zebrafish to explain the phenotypic discrepancies between gene-knockout and gene–knockdown, whereby a deleterious mutation, but not gene-knockdown, can lead to the transcriptional upregulation of related genes, which can assume the function of the mutated gene. This phenomenon was also found in other model systems including mice and Arabidopsis. However, the underlying molecular mechanism of the GCR remains elusive until two papers were published in Nature on April 3, 2019: one from our lab and the other from Stainier's lab. Using different genetic mutants of various genes in zebrafish or culture cells of mice, both of us reveal that the upregulation of compensatory genes is only triggered by mutations that generate a premature termination codon(PTC); the compensatory genes share nucleotide sequence homology to the mutated genes; nonsense m RNA mediated decay pathway(NMD) is essential for the induction of GCR, and the increased transcription of the compensatory genes is accompanied by an enhancement of H3K4 trimethylation(H3K4me3) at their transcription start site(TSS) regions. In this review, we summarize the mechanisms of the GCR proposed in the two studies.
The genetic compensation response(GCR) was firstly described in zebrafish to explain the phenotypic discrepancies between gene-knockout and gene–knockdown, whereby a deleterious mutation, but not gene-knockdown, can lead to the transcriptional upregulation of related genes, which can assume the function of the mutated gene. This phenomenon was also found in other model systems including mice and Arabidopsis. However, the underlying molecular mechanism of the GCR remains elusive until two papers were published in Nature on April 3, 2019: one from our lab and the other from Stainier's lab. Using different genetic mutants of various genes in zebrafish or culture cells of mice, both of us reveal that the upregulation of compensatory genes is only triggered by mutations that generate a premature termination codon(PTC); the compensatory genes share nucleotide sequence homology to the mutated genes; nonsense m RNA mediated decay pathway(NMD) is essential for the induction of GCR, and the increased transcription of the compensatory genes is accompanied by an enhancement of H3K4 trimethylation(H3K4me3) at their transcription start site(TSS) regions. In this review, we summarize the mechanisms of the GCR proposed in the two studies.
引文
[1]Zhu P,Ma Z,Guo L,Zhang W,Zhang Q,Zhao T,Jiang K,Peng J,Chen J.Short body length phenotype is compensated by the upregulation of nidogen family members in a deleterious nid1a mutation of zebrafish.JGenet Genomics,2017,44(11):553-556.
[2]Rossi A,Kontarakis Z,Gerri C,Nolte H,H?lper S,Krüger M,Stainier DY.Genetic compensation induced by deleterious mutations but not gene knockdowns.Nature,2017,524(7564):230-233.
[3]El-Brolosy MA,Kontarakis Z,Rossi A,Kuenne C,Günther S,Fukuda N,Kikhi K,Boezio GLM,Takacs CM,Lai SL,Fukuda R,Gerri C,Giraldez AJ,Stainier DY.Genetic compensation triggered by mutant mRNAdegradation.Nature,2019,568(7751):193-197.
[4]Ma Z,Zhu P,Shi H,Guo L,Zhang Q,Chen Y,Chen S,Zhang Z,Peng J,Chen J.PTC-bearing mRNA elicits a genetic compensation response via Upf3a and COMPASScomponents.Nature,2019,568(7751):259-263.
[5]Chang YF,Imam JS,Wilkinson MF.The nonsensemediated decay RNA surveillance pathway.Annu Rev Biochem,2007,76:51-74.
[6]Conti E,Izaurralde E.Nonsense-mediated mRNA decay:molecular insights and mechanistic variations across species.Curr Opin Cell Biol,2005,17(3):316-325.
[7]Lykke-Andersen J,Shu MD,Steitz JA.Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon.Cell,2000,103(7):1121-1131.
[8]Kunz JB,Neu-Yilik G,Hentze MW,Kulozik AE,Gehring NH.Functions of hUpf3a and hUpf3b in nonsensemediated mRNA decay and translation.RNA,2006,12(6):1015-1022.
[9]Kim VN,Kataoka N,Dreyfuss G.Role of the nonsensemediated decay factor hUpf3 in the splicing-dependent exon-exon junction complex.Science,2001,293(5536):1832-1836.
[10]Chan WK,Bhalla AD,Le Hir H,Nguyen LS,Huang LL,Gécz J,Wilkinson MF.A UPF3-mediated regulatory switch that maintains RNA surveillance.Nat Struct Mol Biol,2009,16(7):747-753.
[11]Shum EY,Jones SH,Shao A,Dumdie J,Krause MD,Chan WK,Lou CH,Espinoza JL,Song HW,Phan MH,Ramaiah M,Huang L,McCarrey JR,Peterson KJ,De Rooij DG,Cook-Andersen H,Wilkinson MF.The antagonistic gene paralogs Upf3a and Upf3b govern nonsense-mediated rna decay.Cell,2016,165(2):382-395.
[12]Tao T,Shi H,Guan Y,Huang D,Chen Y,Lane DP,Chen J,Peng J.Def defines a conserved nucleolar pathway that leads p53 to proteasome-independent degradation.Cell Res,2013,23(5):620-634.
[13]Shen Y,Xiao A,Huang P,Wang W,Zhu Z,Zhang B.TALE nuclease engineering and targeted genome modification.Hereditas(Beijing),2013,35(4):395-409.沈延,肖安,黄鹏,王唯晔,朱作言,张博.类转录激活因子效应物核酸酶(TALEN)介导的基因组定点修饰技术.遗传,2013,35(4):395-409.
[14]Shilatifard A.The COMPASS family of histone H3K4methylases:mechanisms of regulation in development and disease pathogenesis.Annu Rev Biochem,2012,81:65-95.
[15]Hu D,Garruss AS,Gao X,Morgan MA,Cook M,Smith ER,Shilatifard A.The Mll2 branch of the COMPASSfamily regulates bivalent promoters in mouse embryonic stem cells.Nat Struct Mol Biol,2013,20(9):1093-1097.
[16]Hu D,Gao X,Cao K,Morgan MA,Mas G,Smith ER,Volk AG,Bartom ET,Crispino JD,Di Croce L,Shilatifard A.Not all H3K4 methylations are created equal:Mll2/COMPASS dependency in primordial germ cell specification.Mol Cell,2017,65(3):460-475.E6.
[17]De Souza AT,Dai X,Spencer AG,Reppen T,Menzie A,Roesch PL,He Y,Caguyong MJ,Bloomer S,Herweijer H,Wolff JA,Hagstrom JE,Lewis DL,Linsley PS,Ulrich RG.Transcriptional and phenotypic comparisons of Ppara knockout and siRNA knockdown mice.Nucleic Acids Res,2006,34(16):4486-4494.
[18]Gao Y,Zhang Y,Zhang D,Dai X,Estelle M,Zhao Y.Auxin binding protein 1(ABP1)is not required for either auxin signaling or Arabidopsis development.Proc Natl Acad Sci USA,2015,112(7):2275-2280.
[19]Chen R,Shi L,Hakenberg J,Naughton B,Sklar P,Zhang J,Zhou H,Tian L,Prakash O,Lemire M,Sleiman P,Cheng WY,Chen W,Shah H,Shen Y,Fromer M,Omberg L,Deardorff MA,Zackai E,Bobe JR,Levin E,Hudson TJ,Groop L,Wang J,Hakonarson H,Wojcicki A,Diaz GA,Edelmann L,Schadt EE,Friend SH.Analysis of 589,306genomes identifies individuals resilient to severe Mendelian childhood diseases.Nat Biotechnol,2016,34(5):531-538.
[20]Narasimhan VM,Hunt KA,Mason D,Baker CL,Karczewski KJ,Barnes MR,Barnett AH,Bates C,Bellary S,Bockett NA,Giorda K,Griffiths CJ,Hemingway H,Jia Z,Kelly MA,Khawaja HA,Lek M,McCarthy S,McEachan R,O'Donnell-Luria A,Paigen K,Parisinos CA,Sheridan E,Southgate L,Tee L,Thomas M,Xue Y,Schnall-Levin M,Petkov PM,Tyler-Smith C,Maher ER,Trembath RC,MacArthur DG,Wright J,Durbin R,van Heel DA.Health and population effects of rare gene knockouts in adult humans with related parents.Science,2016,352(6284):474-477.
[21]Kok FO,Shin M,Ni CW,Gupta A,Grosse AS,van Impel A,Kirchmaier BC,Peterson-Maduro J,Kourkoulis G,Male I,DeSantis DF,Sheppard-Tindell S,Ebarasi L,Betsholtz C,Schulte-Merker S,Wolfe SA,Lawson ND.Reverse genetic screening reveals poor correlation between morpholino-induced and mutant phenotypes in zebrafish.Dev Cell,2014,32(1):97-108.
[2]Rossi A,Kontarakis Z,Gerri C,Nolte H,H?lper S,Krüger M,Stainier DY.Genetic compensation induced by deleterious mutations but not gene knockdowns.Nature,2017,524(7564):230-233.
[3]El-Brolosy MA,Kontarakis Z,Rossi A,Kuenne C,Günther S,Fukuda N,Kikhi K,Boezio GLM,Takacs CM,Lai SL,Fukuda R,Gerri C,Giraldez AJ,Stainier DY.Genetic compensation triggered by mutant mRNAdegradation.Nature,2019,568(7751):193-197.
[4]Ma Z,Zhu P,Shi H,Guo L,Zhang Q,Chen Y,Chen S,Zhang Z,Peng J,Chen J.PTC-bearing mRNA elicits a genetic compensation response via Upf3a and COMPASScomponents.Nature,2019,568(7751):259-263.
[5]Chang YF,Imam JS,Wilkinson MF.The nonsensemediated decay RNA surveillance pathway.Annu Rev Biochem,2007,76:51-74.
[6]Conti E,Izaurralde E.Nonsense-mediated mRNA decay:molecular insights and mechanistic variations across species.Curr Opin Cell Biol,2005,17(3):316-325.
[7]Lykke-Andersen J,Shu MD,Steitz JA.Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon.Cell,2000,103(7):1121-1131.
[8]Kunz JB,Neu-Yilik G,Hentze MW,Kulozik AE,Gehring NH.Functions of hUpf3a and hUpf3b in nonsensemediated mRNA decay and translation.RNA,2006,12(6):1015-1022.
[9]Kim VN,Kataoka N,Dreyfuss G.Role of the nonsensemediated decay factor hUpf3 in the splicing-dependent exon-exon junction complex.Science,2001,293(5536):1832-1836.
[10]Chan WK,Bhalla AD,Le Hir H,Nguyen LS,Huang LL,Gécz J,Wilkinson MF.A UPF3-mediated regulatory switch that maintains RNA surveillance.Nat Struct Mol Biol,2009,16(7):747-753.
[11]Shum EY,Jones SH,Shao A,Dumdie J,Krause MD,Chan WK,Lou CH,Espinoza JL,Song HW,Phan MH,Ramaiah M,Huang L,McCarrey JR,Peterson KJ,De Rooij DG,Cook-Andersen H,Wilkinson MF.The antagonistic gene paralogs Upf3a and Upf3b govern nonsense-mediated rna decay.Cell,2016,165(2):382-395.
[12]Tao T,Shi H,Guan Y,Huang D,Chen Y,Lane DP,Chen J,Peng J.Def defines a conserved nucleolar pathway that leads p53 to proteasome-independent degradation.Cell Res,2013,23(5):620-634.
[13]Shen Y,Xiao A,Huang P,Wang W,Zhu Z,Zhang B.TALE nuclease engineering and targeted genome modification.Hereditas(Beijing),2013,35(4):395-409.沈延,肖安,黄鹏,王唯晔,朱作言,张博.类转录激活因子效应物核酸酶(TALEN)介导的基因组定点修饰技术.遗传,2013,35(4):395-409.
[14]Shilatifard A.The COMPASS family of histone H3K4methylases:mechanisms of regulation in development and disease pathogenesis.Annu Rev Biochem,2012,81:65-95.
[15]Hu D,Garruss AS,Gao X,Morgan MA,Cook M,Smith ER,Shilatifard A.The Mll2 branch of the COMPASSfamily regulates bivalent promoters in mouse embryonic stem cells.Nat Struct Mol Biol,2013,20(9):1093-1097.
[16]Hu D,Gao X,Cao K,Morgan MA,Mas G,Smith ER,Volk AG,Bartom ET,Crispino JD,Di Croce L,Shilatifard A.Not all H3K4 methylations are created equal:Mll2/COMPASS dependency in primordial germ cell specification.Mol Cell,2017,65(3):460-475.E6.
[17]De Souza AT,Dai X,Spencer AG,Reppen T,Menzie A,Roesch PL,He Y,Caguyong MJ,Bloomer S,Herweijer H,Wolff JA,Hagstrom JE,Lewis DL,Linsley PS,Ulrich RG.Transcriptional and phenotypic comparisons of Ppara knockout and siRNA knockdown mice.Nucleic Acids Res,2006,34(16):4486-4494.
[18]Gao Y,Zhang Y,Zhang D,Dai X,Estelle M,Zhao Y.Auxin binding protein 1(ABP1)is not required for either auxin signaling or Arabidopsis development.Proc Natl Acad Sci USA,2015,112(7):2275-2280.
[19]Chen R,Shi L,Hakenberg J,Naughton B,Sklar P,Zhang J,Zhou H,Tian L,Prakash O,Lemire M,Sleiman P,Cheng WY,Chen W,Shah H,Shen Y,Fromer M,Omberg L,Deardorff MA,Zackai E,Bobe JR,Levin E,Hudson TJ,Groop L,Wang J,Hakonarson H,Wojcicki A,Diaz GA,Edelmann L,Schadt EE,Friend SH.Analysis of 589,306genomes identifies individuals resilient to severe Mendelian childhood diseases.Nat Biotechnol,2016,34(5):531-538.
[20]Narasimhan VM,Hunt KA,Mason D,Baker CL,Karczewski KJ,Barnes MR,Barnett AH,Bates C,Bellary S,Bockett NA,Giorda K,Griffiths CJ,Hemingway H,Jia Z,Kelly MA,Khawaja HA,Lek M,McCarthy S,McEachan R,O'Donnell-Luria A,Paigen K,Parisinos CA,Sheridan E,Southgate L,Tee L,Thomas M,Xue Y,Schnall-Levin M,Petkov PM,Tyler-Smith C,Maher ER,Trembath RC,MacArthur DG,Wright J,Durbin R,van Heel DA.Health and population effects of rare gene knockouts in adult humans with related parents.Science,2016,352(6284):474-477.
[21]Kok FO,Shin M,Ni CW,Gupta A,Grosse AS,van Impel A,Kirchmaier BC,Peterson-Maduro J,Kourkoulis G,Male I,DeSantis DF,Sheppard-Tindell S,Ebarasi L,Betsholtz C,Schulte-Merker S,Wolfe SA,Lawson ND.Reverse genetic screening reveals poor correlation between morpholino-induced and mutant phenotypes in zebrafish.Dev Cell,2014,32(1):97-108.
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