title: The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation.
abstract: Alternative splicing (AS) of pre-mRNA is utilized by higher eukaryotes to achieve increased transcriptome and proteomic complexity. The serine/arginine (SR) splicing factors regulate tissue- or cell-type-specific AS in a concentration- and phosphorylation-dependent manner. However, the mechanisms that modulate the cellular levels of active SR proteins remain to be elucidated. In the present study, we provide evidence for a role for the long nuclear-retained regulatory RNA (nrRNA), MALAT1 in AS regulation. MALAT1 interacts with SR proteins and influences the distribution of these and other splicing factors in nuclear speckle domains. Depletion of MALAT1 or overexpression of an SR protein changes the AS of a similar set of endogenous pre-mRNAs. Furthermore, MALAT1 regulates cellular levels of phosphorylated forms of SR proteins. Taken together, our results suggest that MALAT1 regulates AS by modulating the levels of active SR proteins. Our results further highlight the role for an nrRNA in the regulation of gene expression.
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Vidisha
authors.initials: V
authors.lastname: Tripathi
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ellis
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shen
authors.forename: David Y
authors.initials: DY
authors.lastname: Song
authors.forename: Qun
authors.initials: Q
authors.lastname: Pan
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Watt
authors.forename: Susan M
authors.initials: SM
authors.lastname: Freier
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Alok
authors.initials: A
authors.lastname: Sharma
authors.forename: Paula A
authors.initials: PA
authors.lastname: Bubulya
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
authors.forename: Supriya G
authors.initials: SG
authors.lastname: Prasanth
authors.forename: Kannanganattu V
authors.initials: KV
authors.lastname: Prasanth
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D042581:Intranuclear Space / Q000378:metabolism; D051379:Mice; D015778:Minor Histocompatibility Antigens; D008938:Mitosis / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D012322:RNA Precursors / Q000378:metabolism; D000072260:RNA Splicing Factors; D022661:RNA, Untranslated / Q000235:genetics / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D038621:Regulatory Sequences, Ribonucleic Acid / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; C408605:PRPF6 protein, human; D012322:RNA Precursors; D000072260:RNA Splicing Factors; D022661:RNA, Untranslated; D016601:RNA-Binding Proteins; D038621:Regulatory Sequences, Ribonucleic Acid; C088203:SON protein, human; D014157:Transcription Factors; D000068103:Serine-Arginine Splicing Factors
references.citation: EMBO J. 1998 Nov 2;17(21):6359-67
references.pmid: 9799243
references.citation: Genes Dev. 2007 Jan 1;21(1):11-42
references.pmid: 17210785
references.citation: Cell. 2009 Sep 4;138(5):898-910
references.pmid: 19737518
references.citation: Cell. 2008 Nov 28;135(5):919-32
references.pmid: 19041754
references.citation: EMBO J. 1993 Dec;12(12):4715-26
references.pmid: 8223480
references.citation: Nature. 2009 Mar 12;458(7235):223-7
references.pmid: 19182780
references.citation: Prog Nucleic Acid Res Mol Biol. 2004;78:37-88
references.pmid: 15210328
references.citation: Mol Cell. 2003 Jul;12(1):5-14
references.pmid: 12887888
references.citation: EMBO J. 2004 Jul 7;23(13):2651-63
references.pmid: 15215892
references.citation: Genes Dev. 2007 Nov 15;21(22):2963-75
references.pmid: 17978102
references.citation: Nature. 1990 Feb 1;343(6257):437-41
references.pmid: 2137203
references.citation: Cell. 2009 Feb 20;136(4):642-55
references.pmid: 19239886
references.citation: Mol Cell. 2009 Mar 27;33(6):717-26
references.pmid: 19217333
references.citation: Nat Genet. 2008 Dec;40(12):1413-5
references.pmid: 18978789
references.citation: Mol Biol Cell. 2003 Mar;14(3):1043-57
references.pmid: 12631722
references.citation: PLoS Genet. 2009 Apr;5(4):e1000459
references.pmid: 19390609
references.citation: Genes Dev. 1997 Feb 1;11(3):334-44
references.pmid: 9030686
references.citation: Genome Res. 2009 Mar;19(3):381-94
references.pmid: 19116412
references.citation: PLoS Biol. 2010 May 18;8(5):e1000371
references.pmid: 20502517
references.citation: Anat Rec A Discov Mol Cell Evol Biol. 2006 Jul;288(7):664-75
references.pmid: 16761280
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):716-21
references.pmid: 18184812
references.citation: Nat Struct Mol Biol. 2007 Mar;14(3):185-93
references.pmid: 17310252
references.citation: Nucleic Acids Res. 2002 Jan 1;30(1):207-10
references.pmid: 11752295
references.citation: Biochem J. 2009 Jan 1;417(1):15-27
references.pmid: 19061484
references.citation: Science. 2008 Mar 28;319(5871):1787-9
references.pmid: 18369136
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9666-70
references.pmid: 15210956
references.citation: Cell. 2006 Jul 14;126(1):37-47
references.pmid: 16839875
references.citation: Genome Res. 2009 Mar;19(3):347-59
references.pmid: 19106332
references.citation: Dev Cell. 2009 Nov;17(5):639-47
references.pmid: 19922869
references.citation: Nat Rev Genet. 2009 Mar;10(3):155-9
references.pmid: 19188922
references.citation: J Cell Sci. 2007 Aug 1;120(Pt 15):2498-506
references.pmid: 17623775
references.citation: J Mol Biol. 2000 May 12;298(4):567-75
references.pmid: 10788320
references.citation: Mol Cell. 2006 Mar 3;21(5):617-28
references.pmid: 16507360
references.citation: J Cell Sci. 2000 Oct;113 Pt 19:3485-97
references.pmid: 10984439
references.citation: RNA. 1997 Dec;3(12):1456-67
references.pmid: 9404896
references.citation: J Biol Chem. 2008 Jan 18;283(3):1223-7
references.pmid: 18024427
references.citation: J Cell Biol. 1997 Jul 28;138(2):225-38
references.pmid: 9230067
references.citation: Nat Rev Genet. 2010 Jan;11(1):75-87
references.pmid: 20019688
references.citation: Mol Cell. 2004 Dec 22;16(6):929-41
references.pmid: 15610736
references.citation: Nature. 2008 Nov 27;456(7221):470-6
references.pmid: 18978772
references.citation: Oncogene. 2007 Feb 8;26(6):851-8
references.pmid: 16878148
references.citation: Genome Res. 2006 Jan;16(1):11-9
references.pmid: 16344565
references.citation: Mol Cell Biol. 2002 Oct;22(19):6871-82
references.pmid: 12215544
references.citation: Cell. 2006 Dec 1;127(5):1071
references.pmid: 17129789
references.citation: BMC Genomics. 2007 Feb 01;8:39
references.pmid: 17270048
references.citation: J Cell Biol. 1998 Oct 19;143(2):297-307
references.pmid: 9786943
references.citation: Nat Biotechnol. 2009 Jul;27(7):667-70
references.pmid: 19561594
references.citation: Nat Rev Mol Cell Biol. 2003 Aug;4(8):605-12
references.pmid: 12923522
references.citation: Science. 2002 May 3;296(5569):916-9
references.pmid: 11988577
references.citation: Mol Cell. 2007 Oct 12;28(1):79-90
references.pmid: 17936706
references.citation: Mol Cell. 2009 Aug 28;35(4):467-78
references.pmid: 19716791
references.citation: Genes Dev. 2009 Jul 1;23(13):1494-504
references.pmid: 19571179
references.citation: Mol Biol Cell. 2010 Feb 15;21(4):650-63
references.pmid: 20053686
references.citation: Cell. 2005 Oct 21;123(2):249-63
references.pmid: 16239143
references.citation: Bioinformatics. 2006 Mar 1;22(5):606-13
references.pmid: 16403798
references.citation: Oncogene. 2003 Sep 11;22(39):8031-41
references.pmid: 12970751
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2525-30
references.pmid: 19188602
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15042-7
references.pmid: 16210245
references.citation: Genes Dev. 2010 Jun 1;24(11):1073-4
references.pmid: 20516191
references.citation: J Cell Sci. 2000 Jun;113 ( Pt 11):1841-9
references.pmid: 10806095
references.citation: Adv Exp Med Biol. 2007;623:107-22
references.pmid: 18380343
references.citation: Genes Dev. 2009 Feb 15;23(4):482-95
references.pmid: 19240134
references.citation: FEBS J. 2010 Feb;277(4):856-66
references.pmid: 20082635
references.citation: Hum Mol Genet. 2006 Aug 15;15(16):2490-508
references.pmid: 16825284