细胞核内小干扰RNA介导的表观遗传和基因表达调控
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摘要
RNA干扰(RNAi)是真核生物中一个非常广泛而且保守的基因表达调节机制.长度为20~30个核苷酸的具有调控作用的小RNA广泛存在于几乎所有的真核细胞中,这些小RNA参与和调控许多基本的生命过程,如异染色质的形成、基因组稳定性的维持、发育的时空调节、细胞命运的决定、DNA的损伤与修复反应,以及抗病毒反应等.这些小RNA的产生和调节的失衡往往会导致一系列重大疾病的发生与发展.RNAi在细胞质里主要是通过抑制翻译和诱导靶标mRNA的降解来进行.在细胞核中,RNAi则有多种作用方式.本文将重点阐述小RNA在细胞核里的基因表达调控的分子机制,包括诱导异染色质形成、介导表观遗传修饰、调控染色体分离,以及调控转录和选择性剪切等过程.
RNA interference(RNAi) is a widely conserved gene regulation mechanism in eukaryotes.Small regulatory RNAs(20-30 nt in length) are widely present in nearly all eukaryote cells.These small regulatory RNAs are engaged in many essential biological processes,including but not limited to heterochromatin formation,maintenance of genome integrity,spatiotemporal developmental regulation,cell fate decisions,DNA repair,and antiviral reactions.Dysregulation of the biogenesis and homeostasis of these small regulatory RNAs can often lead to a variety of severe human diseases.In the cytoplasm,RNAi usually act through inhibiting protein translation or inducing mRNA degradation.In the nucleus,RNAi can act via a number of mechanisms.In this review,we will focus on the mechanisms of small RNA-mediated gene regulation in the nucleus,including heterochromatin formation,epigenetic modification,chromosome segregation,transcriptional regulation,and alternative splicing.
RNA interference(RNAi) is a widely conserved gene regulation mechanism in eukaryotes.Small regulatory RNAs(20-30 nt in length) are widely present in nearly all eukaryote cells.These small regulatory RNAs are engaged in many essential biological processes,including but not limited to heterochromatin formation,maintenance of genome integrity,spatiotemporal developmental regulation,cell fate decisions,DNA repair,and antiviral reactions.Dysregulation of the biogenesis and homeostasis of these small regulatory RNAs can often lead to a variety of severe human diseases.In the cytoplasm,RNAi usually act through inhibiting protein translation or inducing mRNA degradation.In the nucleus,RNAi can act via a number of mechanisms.In this review,we will focus on the mechanisms of small RNA-mediated gene regulation in the nucleus,including heterochromatin formation,epigenetic modification,chromosome segregation,transcriptional regulation,and alternative splicing.
引文
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2 Feng X,Guang S.Small RNAs,RNAi and the inheritance of gene silencing in Caenorhabditis elegans.J Genet Genomics,2013,40:153-160
3 Harmon G J,Rivas F V,Murchison E P,et al.The expanding universe of noncoding RNAs.Cold Spring Harb Symp Quant Biol,2006,71:551-564
4 Ketting R F.The many faces of RNAi.Dev Cell,2011,20:148-161
5 Bernstein E,Allis C D.RNA meets chromatin.Genes Dev,2005,19:1635-1655
6 Carthew R W,Sontheimer E J.Origins and mechanisms of miRNAs and siRNAs.Cell,2009,136:642-655
7 Czech B,Harmon G J.Small RNA sorting:matchmaking for Argonautes.Nat Rev Genet,2011,12:19-31
8 Castel S E,Martienssen R A.RNA interference in the nucleus:roles for small RNAs in transcription,epigenetics and beyond.Nat Rev Genet,2013,14:100-112
9 Knight S W,Bass B L.A role for the RNaseⅢenzyme DCR-1 in RNA interference and germ line development in Caenorhabditis elegans.Science,2001,293:2269-2271
10 Ketting R F,Fischer S E,Bernstein E,et al.Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C.elegans.Genes Dev,2001,15:2654-2659
11 Kanellopoulou C,Muljo S A,Kung A L,et al.Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing.Genes Dev,2005,19:489-501
12 Baulcombe D.RNA silencing in plants.Nature,2004,431:356-363
13 Vaishnaw A K,Gollob J,Gamba-Vitalo C,et al.A status report on RNAi therapeutics.Silence,2010,1:14
14 Burger K,Gullerova M.Swiss army knives:non-canonical functions of nuclear Drosna and Dicer.Nat Rev Mol Cell Biol,2015,16:417-430
15 Matzke M A,Birchler J A.RNAi-mediated pathways in the nucleus.Nat Rev Genet,2005,6:24-35
16 Kalantari R,Chiang C M,Corey D R.Regulation of mammalian transcription and splicing by nuclear RNAi.Nucleic Acids Res,2016,44:524-537
17 Feng X Z,Guang S H.Non-coding RNAs mediate the rearrangements of genomic DNA in ciliates.Sci China Life Sci,2013,56:937-943
18 Swart E C,Bracht J R,Magrini V,et al.The Oxytricha trifallax macronuclear genome:a complex eukaryotic genome with 16,000 tiny chromosomes.PLoS Biol,2013,11:el001473
19 Li L C.Chromatin remodeling by the small RNA machinery in mammalian cells.Epigenetics,2014,9:45-52
20 Moazed D.Small RNAs in transcriptional gene silencing and genome defence.Nature,2009,457:413-420
21 Cam H P.Roles of RNAi in chromatin regulation and epigenetic inheritance.Epigenomics,2010,2:613-626
22 Zilberman D,Cao X,Jacobsen S E.ARGONAUTE4 control of locus-specific siRNA accumulation and DNA and histone methylation.Science,2003,299:716-719
23 McCue A D,Panda K,Nuthikattu S,et al.ARGONAUTE 6 bridges transposable element mRNA-derived siRNAs to the establishment of DNA methylation.EMBO J,2015,34:20-35
24 Underwood C J,Martienssen R A.Argonautes team up to silence transposable elements in Arabidopsis.EMBO J,2015,34:579-580
25 Duan C G,Zhang H,Tang K,et al.Specific but interdependent functions for Arabidopsis AGO4 and AGO6 in RNA-directed DNA methylation.EMBO J,2015,34:581-592
26 Zhao Y,Chen X.Non-coding RNAs and DNA methylation in plants.Natl Sci Rev,2014,1:219-229
27毛颖波,薛学义,陈晓亚.植物小RNA与RNA干扰:生物学功能与应用前景.中国科学C辑:生命科学,2009,39:31-43
28张新岩,朱颖,吴辉辉,等.植物转录后水平基因沉默:调控基因表达的一把双刃剑.中国科学:生命科学,2016,46:716-722
29 Kasschau K D,Fahlgren N,Chapman E J,et al.Genome-wide profiling and analysis of Arabidopsis siRNAs.PLoS Biol,2007,5:e57
30 Zhang X,Henderson I R,Lu C,et al.Role of RNA polymerase IV in plant small RNA metabolism.Proc Natl Acad Sci USA,2007,104:4536-4541
31 Zhu Y,Rowley M J,Bohmdorfer G,et al.A SWI/SNF chromatin-remodeling complex acts in noncoding RNA-mediated transcriptional silencing.Mol Cell,2013,49:298-309
32 Matzke M A,MosherR A.RNA-directed DNA methylation:an epigenetic pathway of increasing complexity.Nat Rev Genet,2014,15:394-408
33 Nuthikattu S,McCue AD,Panda K,et al.The initiation of epigenetic silencing of active transposable elements is triggered by RDR6 and 21-22nucleotide small interfering RNAs.Plant Physiol,2013,162:116-131
34 Halic M,Moazed D.Dicer-independent primal RNAs trigger RNAi and heterochromatin formation.Cell,2010,140:504-516
35 Volpe T A,Kidner C,Hall I M,et al.Regulation of heterochromatic silencing and histone H3 Lysine-9 methylation by RNAi.Science,2002,297:1833-1837
36 Verdel A,Jia S,Gerber S,et al.RNAi-mediated targeting of heterochromatin by the RITS complex.Science,2004,303:672-676
37 Martienssen R,Moazed D.RNAi and heterochromatin assembly.Cold Spring Harb Perspect Biol,2015,7:a019323
38 WuL,Mao L,Qi Y.Roles of dicer-like and argonaute proteins in TAS-derived small interfering RNA-triggered DNA methylation.Plant Physiol,2012,160:990-999
39 HolochD,MoazedD.RNA-mediated epigenetic regulation of gene expression.NatRev Genet,2015,16:71-84
40 Bayne E H,White S A,Kagansky A,et al.Stc1:a critical link between RNAi and chromatin modification required for heterochromatin integrity.Cell,2010,140:666-677
41 Jia S,Kobayashi R,Grewal S I S.Ubiquitin ligase component Cul4 associates with Clr4 histone methyltransferase to assemble heterochromatin.Nat Cell Biol,2005,7:1007-1013
42 Horn P J,Bastie J N,Peterson C L.A Rik1-associated,cullin-dependent E3 ubiquitin ligase is essential for heterochromatin formation.Genes Dev,2005,19:1705-1714
43 Li H,Motamedi M R,Yip C K,et al.An alpha motif at Tas3 C terminus mediates RITS cis spreading and promotes heterochromatic gene silencing.Mol Cell,2009,34:155-167
44 Schalch T,Job G,Shanker S,et al.The Chpl-Tas3 core is a multifunctional platform critical for gene silencing by RITS.Nat Struct Mol Biol,2011,18:1351-1357
45 Lee YC G.The role of piRNA-mediated epigenetic silencing in the population dynamics of transposable elements in Drosophila melanoeaster.PLoS Genet,2015,11:el005269
46 Fukaya T,Tomari Y.MicroRNAs mediate gene silencing via multiple different pathways in Drosophila.Mol Cell,2012,48:825-836
47 Wang S H,Elgin S C R.Drosophila Piwi functions downstream of piRNA production mediating a chromatin-based transposon silencing mechanism in female germ line.Proc Natl Acad Sci USA,2011,108:21164-21169
48 Kang H,McElroy K A,Jung Y L,et al.Sex comb on midleg(Scm)is a functional link between PcG-repressive complexes in Drosophila.Genes Dev,2015,29:1136-1150
49 Lo Sardo F,Lanzuolo C,Comoglio F,et al.PcG-mediated higher-order chromatin structures modulate replication programs at the Drosophila BX-C.PLoS Genet,2013,9:el003283
50 Gu S G,Pak J,Guang S,et al.Amplification of siRNA in Caenorhabditis elegans generates a transgenerational sequence-targeted histone H3lysine 9 methylation footprint.Nat Genet,2012,44:157-164
51 Guang S,Bochner A F,Burkhart K B,et al.Small regulatory RNAs inhibit RNA polymerase II during the elongation phase of transcription.Nature,2010,465:1097-1101
52 Burkhart K B,Guang S,Buckley B A,et al.A pre-mRNA-associating factor links endogenous siRNAs to chromatin regulation.PLoS Genet,2011,7:el002249
53 Guang S,Bochner A F,Pavelec D M,et al.An Argonaute transports siRNAs from the cytoplasm to the nucleus.Science,2008,321:537-541
54 Mao H,Zhu C,Zong D,et al.The Nrde pathway mediates small-RNA-directed histone H3 Lysine 27 trimethylation in Caenorhabditis elegans.Curr Biol,2015,25:2398-2403
55 Ashe A,Sapetschnig A,Weick E M,et al.piRNAs can trigger a multigenerational epigenetic memory in the germline of C.elegans.Cell,2012,150:88-99
56 Vastenhouw N L,Brunschwig K,Okihara K L,et al.Gene expression:long-term gene silencing by RNAi.Nature,2006,442:882-882
57 Grishok A,Sinskey JL,SharpP A.Transcriptional silencing of atransgene by RNAi in the soma of C.elegans.Genes Dev,2005,19:683-696
58 Zeng Y,Cullen B R.RNA interference in human cells is restricted to the cytoplasm.RNA,2002,8:855-860
59 Sen G L,Blau H M.Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies.Nat Cell Biol,2005,7:633-636
60 Kim D H,Villeneuve L M,Morris K V,et al.Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells.Nat Struct Mol Biol,2006,13:793-797
61 Beckedorff F C,Ayupe A C,Crocci-Souza R,et al.The intronic long noncoding RNA ANRASSF1 recruits PRC2 to the RASSF1A promoter,reducing the expression of RASSF1A and increasing cell proliferation.PLoS Genet,2013,9:el003705
62 Lanzuolo C,Lo Sardo F,Diamantini A,et al.PcG complexes set the stage for epigenetic inheritance of gene silencing in early S phase before replication.PLoS Genet,2011,7:el002370
63 Huang C,Wang X,Liu X,et al.RNAi pathway participates in chromosome segregation in mammalian cells.Cell Discov,2015,1:15029
64 Westhorpe F G,Straight A F.Functions of the centromere and kinetochore in chromosome segregation.Curr Opin Cell Biol,2013,25:334-340
65 Chan F L,Wong L H.Transcription in the maintenance of centromere chromatin identity.Nucleic Acids Res,2012,40:11178-11188
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