旁粒组分Nono在小鼠胚胎干细胞中的转录调控机制
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摘要
旁粒及其组分在肿瘤发生和诸多正常的生物学功能中都扮演了重要的角色,但对于其具体的作用机制仍然缺乏了解。在人和小鼠的胚胎干细胞中,旁粒的关键结构组分长链非编码RNA NEAT1_v2并不表达,只表达其短变体NEAT1_v1和3种旁粒蛋白组分——NONO、SFPQ和PSPC1,提示这些组分可能具有独立于经典旁粒结构之外的功能。蓝斐课题组依托国家基金委"细胞编程和重编程的表观遗传机制"重大研究计划,在此方向上开展了系统性的研究,并获得了进展:首次发现旁粒蛋白组分Nono和Erk相互作用,共同结合在小鼠胚胎干细胞的双价结构域基因(bivalent genes)的启动子区,并参与Mek/Erk信号途径调控靶基因的待激活状态;研究还发现,Nono缺失的m ESC具有更强的自我更新能力,对于胚胎干细胞的体外培养有重要的参考价值。对本领域的最新进展以及复旦大学蓝斐课题组的相关原创性工作进行综述。
Paraspeckle and its components play important roles in various biological processes, and their malfunction could lead to diseases such as cancer. In human and mouse embryonic stem cells(ESCs), lnc RNA NEAT1_v2, the key structural component of paraspeckle stays transcriptionally silent; while its short isoform NEAT1_v1 and three paraspeckle protein components, NONO, SFQP and PSPC1, are well expressed, indicating paraspeckle independent functions. Supported by a NSFC grant focusing on "The Epigenetic Mechanisms of Cell Programming and Reprogramming", our study uncovered a role of Nono in interacting with Erk and regulating the poised state of RNA polymerase II at bivalent genes in m ESCs. Importantly, Nono loss led to an impaired activation of Erk signaling and robust self-renewal of m ESC. These findings reveal a previously underappreciated function of paraspeckle components in regulating transcription in chromatin environment and provide alternative approaches to obtain ESCs with robust self-renewing ability. Here, we will debrief the recent advancement in the area and summarize our major findings from the project.
Paraspeckle and its components play important roles in various biological processes, and their malfunction could lead to diseases such as cancer. In human and mouse embryonic stem cells(ESCs), lnc RNA NEAT1_v2, the key structural component of paraspeckle stays transcriptionally silent; while its short isoform NEAT1_v1 and three paraspeckle protein components, NONO, SFQP and PSPC1, are well expressed, indicating paraspeckle independent functions. Supported by a NSFC grant focusing on "The Epigenetic Mechanisms of Cell Programming and Reprogramming", our study uncovered a role of Nono in interacting with Erk and regulating the poised state of RNA polymerase II at bivalent genes in m ESCs. Importantly, Nono loss led to an impaired activation of Erk signaling and robust self-renewal of m ESC. These findings reveal a previously underappreciated function of paraspeckle components in regulating transcription in chromatin environment and provide alternative approaches to obtain ESCs with robust self-renewing ability. Here, we will debrief the recent advancement in the area and summarize our major findings from the project.
引文
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[2]Fox AH,Lam YW,Leung AK,et al.Paraspeckles:a novel nuclear domain.Curr Biol,2002,12:13-25
[3]Andersen JS,Lyon CE,Fox AH,et al.Directed proteomic analysis of the human nucleolus.Curr Biol,2002,12:1-11
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[6]Myojin R,Kuwahara S,Yasaki T,et al.Expression and functional significance of mouse paraspeckle protein 1 on spermatogenesis.Biol Reprod,2004,71:926-32
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[8]Li R,Harvey AR,Hodgetts SI,et al.Functional dissection of NEAT1 using genome editing reveals substantial localization of the NEAT1_1 isoform outside paraspeckles.RNA:New York,2017,23:872-81
[9]Ghosal S,Das S,Chakrabarti J.Long noncoding RNAs:new players in the molecular mechanism for maintenance and differentiation of pluripotent stem cells.Stem Cell Dev,2013,22:2240-53
[10]Fox AH,Lamond AI.Paraspeckles.Cold Spring Harb Perspect Biol,2010,2:a000687
[11]Scadden D.A NEAT way of regulating nuclear export of mRNAs.Mol Cell,2009,35:395-6
[12]Jiang L,Shao C,Wu QJ,et al.NEAT1 scaffolds RNAbinding proteins and the Microprocessor to globally enhance pri-miRNA processing.Nat Struct Mol Biol,2017,24:816-24
[13]Jaafar L,Li Z,Li S,et al.SFPQ?NONO and XLF function separately and together to promote DNA double-strand break repair via canonical nonhomologous end joining.Nucleic Acids Res,2017,45:1848-59
[14]Salton M,Wang SY.Involvement of matrin 3 and SFPQ/NONO in the DNA damage response.Cell Cycle,2010,9:1568-76
[15]Krietsch J,Caron MC,GagnéJP,et al.PARP activation regulates the RNA-binding protein NONO in the DNAdamage response to DNA double-strand breaks.Nucleic Acids Res,2012,40:10287-301
[16]Kowalska E,Ripperger JA,Hoegger DC,et al.NONOcouples the circadian clock to the cell cycle.Proc Natl Acad Sci USA,2013,110:1592-9
[17]Torres M,Becquet D,Blanchard MP,et al.Paraspeckles as rhythmic nuclear mRNA anchorages responsible for circadian gene expression.Nucleus,2017,8:249-54
[18]Amelio AL,Miraglia LJ,Conkright JJ,et al.A coactivator trap identifies NONO(p54nrb)as a component of the cAMP-signaling pathway.Proc Natl Acad Sci USA,2007,104:20314-9
[19]Jia YL,Sewer MB.p54nrb/NONO regulates cyclic AMPdependent glucocorticoid production by modulating phosphodiesterase mRNA splicing and degradation.Mol Cell Biol,2015,35:1223-37
[20]West J,Davis C,Sunwoo H,et al.The long noncoding RNAs NEAT1 and MALAT1 bind active chromatin sites.Mol Cell,2014,55:791-802
[21]Emili A,Shales M,McCracken S,et al.Splicing and transcription-associated proteins PSF and p54 nrb/nonObind to the RNA polymerase II CTD.RNA,2002,8:1102-11
[22]Wang Z,Fan P,Zhao Y,et al.NEAT1 modulates herpes simplex virus-1 replication by regulating viral gene transcription.Cell Mol Life Sci,2017,74:1117-31
[23]Zhu Z,Zhao X,Zhao L,et al.p54nrb/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A.Oncogene,2015,35:1399-410
[24]Chakravarty D,Sboner A,Nair SS,et al.The oestrogen receptorα-regulated lncRNA NEAT1 is a critical modulator of prostate cancer.Nat Commun,2014,5:5383
[25]Rheinbay E,Parasuraman P,Grimsby J,et al.Recurrent and functional regulatory mutations in breast cancer.Nature,2017,547:55-60
[26]Mello SS,Sinow C,Raj N,et al.Neat1 is a p53-inducible lincRNA essential for transformation suppression.Genes Dev,2017,31:1095-108
[27]Ma C,Karwacki-Neisius V,Tang H,et al.Nono,a bivalent domain factor,regulates erk signaling and mouse embryonic stem cell pluripotency.Cell Rep,2016,17:997-1007
[28]Niwa H,Ogawa K,Shimosato D,et al.A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells.Nature,2009,460:118-22
[29]Ying QL,Wray J,Nichols J,et al.The ground state of embryonic stem cell self-renewal.Nature,2008,453:519-23
[30]Martello G,Smith A.The nature of embryonic stem cells.Annu Rev Cell Dev Biol,2014,30:647-75
[31]Torres-Padilla ME,Chambers I.Transcription factor heterogeneity in pluripotent stem cells:a stochastic advantage.Development,2014,141:2173-81
[32]Bernstein BE,Mikkelsen TS,Xie X,et al.A bivalent chromatin structure marks key developmental genes in embryonic stem cells.Cell,2006,125:315-26
[33]Tee WW,Shen SS,Oksuz O,et al.Erk1/2 activity promotes chromatin features and RNAPII phosphorylation at developmental promoters in mouse ESCs.Cell,2014,156:678-90
[2]Fox AH,Lam YW,Leung AK,et al.Paraspeckles:a novel nuclear domain.Curr Biol,2002,12:13-25
[3]Andersen JS,Lyon CE,Fox AH,et al.Directed proteomic analysis of the human nucleolus.Curr Biol,2002,12:1-11
[4]Prasanth KV,Prasanth SG,Xuan Z,et al.Regulating gene expression through RNA nuclear retention.Cell,2005,123:249-63
[5]Fox AH,Bond CS,Lamond AI.P54nrb forms a heterodimer with PSP1 that localizes to paraspeckles in an RNA-dependent manner.Mol Biol Cell,2005,16:5304-15
[6]Myojin R,Kuwahara S,Yasaki T,et al.Expression and functional significance of mouse paraspeckle protein 1 on spermatogenesis.Biol Reprod,2004,71:926-32
[7]Clemson CM,Hutchinson JN,Sara SA,et al.An architectural role for a nuclear noncoding RNA:RNA is essential for the structure of paraspeckles.Mol Cell,2009,33:717-26
[8]Li R,Harvey AR,Hodgetts SI,et al.Functional dissection of NEAT1 using genome editing reveals substantial localization of the NEAT1_1 isoform outside paraspeckles.RNA:New York,2017,23:872-81
[9]Ghosal S,Das S,Chakrabarti J.Long noncoding RNAs:new players in the molecular mechanism for maintenance and differentiation of pluripotent stem cells.Stem Cell Dev,2013,22:2240-53
[10]Fox AH,Lamond AI.Paraspeckles.Cold Spring Harb Perspect Biol,2010,2:a000687
[11]Scadden D.A NEAT way of regulating nuclear export of mRNAs.Mol Cell,2009,35:395-6
[12]Jiang L,Shao C,Wu QJ,et al.NEAT1 scaffolds RNAbinding proteins and the Microprocessor to globally enhance pri-miRNA processing.Nat Struct Mol Biol,2017,24:816-24
[13]Jaafar L,Li Z,Li S,et al.SFPQ?NONO and XLF function separately and together to promote DNA double-strand break repair via canonical nonhomologous end joining.Nucleic Acids Res,2017,45:1848-59
[14]Salton M,Wang SY.Involvement of matrin 3 and SFPQ/NONO in the DNA damage response.Cell Cycle,2010,9:1568-76
[15]Krietsch J,Caron MC,GagnéJP,et al.PARP activation regulates the RNA-binding protein NONO in the DNAdamage response to DNA double-strand breaks.Nucleic Acids Res,2012,40:10287-301
[16]Kowalska E,Ripperger JA,Hoegger DC,et al.NONOcouples the circadian clock to the cell cycle.Proc Natl Acad Sci USA,2013,110:1592-9
[17]Torres M,Becquet D,Blanchard MP,et al.Paraspeckles as rhythmic nuclear mRNA anchorages responsible for circadian gene expression.Nucleus,2017,8:249-54
[18]Amelio AL,Miraglia LJ,Conkright JJ,et al.A coactivator trap identifies NONO(p54nrb)as a component of the cAMP-signaling pathway.Proc Natl Acad Sci USA,2007,104:20314-9
[19]Jia YL,Sewer MB.p54nrb/NONO regulates cyclic AMPdependent glucocorticoid production by modulating phosphodiesterase mRNA splicing and degradation.Mol Cell Biol,2015,35:1223-37
[20]West J,Davis C,Sunwoo H,et al.The long noncoding RNAs NEAT1 and MALAT1 bind active chromatin sites.Mol Cell,2014,55:791-802
[21]Emili A,Shales M,McCracken S,et al.Splicing and transcription-associated proteins PSF and p54 nrb/nonObind to the RNA polymerase II CTD.RNA,2002,8:1102-11
[22]Wang Z,Fan P,Zhao Y,et al.NEAT1 modulates herpes simplex virus-1 replication by regulating viral gene transcription.Cell Mol Life Sci,2017,74:1117-31
[23]Zhu Z,Zhao X,Zhao L,et al.p54nrb/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A.Oncogene,2015,35:1399-410
[24]Chakravarty D,Sboner A,Nair SS,et al.The oestrogen receptorα-regulated lncRNA NEAT1 is a critical modulator of prostate cancer.Nat Commun,2014,5:5383
[25]Rheinbay E,Parasuraman P,Grimsby J,et al.Recurrent and functional regulatory mutations in breast cancer.Nature,2017,547:55-60
[26]Mello SS,Sinow C,Raj N,et al.Neat1 is a p53-inducible lincRNA essential for transformation suppression.Genes Dev,2017,31:1095-108
[27]Ma C,Karwacki-Neisius V,Tang H,et al.Nono,a bivalent domain factor,regulates erk signaling and mouse embryonic stem cell pluripotency.Cell Rep,2016,17:997-1007
[28]Niwa H,Ogawa K,Shimosato D,et al.A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells.Nature,2009,460:118-22
[29]Ying QL,Wray J,Nichols J,et al.The ground state of embryonic stem cell self-renewal.Nature,2008,453:519-23
[30]Martello G,Smith A.The nature of embryonic stem cells.Annu Rev Cell Dev Biol,2014,30:647-75
[31]Torres-Padilla ME,Chambers I.Transcription factor heterogeneity in pluripotent stem cells:a stochastic advantage.Development,2014,141:2173-81
[32]Bernstein BE,Mikkelsen TS,Xie X,et al.A bivalent chromatin structure marks key developmental genes in embryonic stem cells.Cell,2006,125:315-26
[33]Tee WW,Shen SS,Oksuz O,et al.Erk1/2 activity promotes chromatin features and RNAPII phosphorylation at developmental promoters in mouse ESCs.Cell,2014,156:678-90