Wiskott-Aldrich syndrome protein forms nuclear condensates and regulates alternative splicing.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 06 2022
25 06 2022
Historique:
received:
06
03
2021
accepted:
06
06
2022
entrez:
25
6
2022
pubmed:
26
6
2022
medline:
29
6
2022
Statut:
epublish
Résumé
The diverse functions of WASP, the deficiency of which causes Wiskott-Aldrich syndrome (WAS), remain poorly defined. We generated three isogenic WAS models using patient induced pluripotent stem cells and genome editing. These models recapitulated WAS phenotypes and revealed that WASP deficiency causes an upregulation of numerous RNA splicing factors and widespread altered splicing. Loss of WASP binding to splicing factor gene promoters frequently leads to aberrant epigenetic activation. WASP interacts with dozens of nuclear speckle constituents and constrains SRSF2 mobility. Using an optogenetic system, we showed that WASP forms phase-separated condensates that encompasses SRSF2, nascent RNA and active Pol II. The role of WASP in gene body condensates is corroborated by ChIPseq and RIPseq. Together our data reveal that WASP is a nexus regulator of RNA splicing that controls the transcription of splicing factors epigenetically and the dynamics of the splicing machinery through liquid-liquid phase separation.
Identifiants
pubmed: 35752626
doi: 10.1038/s41467-022-31220-8
pii: 10.1038/s41467-022-31220-8
pmc: PMC9233711
doi:
Substances chimiques
RNA Splicing Factors
0
RNA-Binding Proteins
0
Wiskott-Aldrich Syndrome Protein
0
RNA Polymerase II
EC 2.7.7.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3646Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s).
Références
Sci Transl Med. 2010 Jun 23;2(37):37ra44
pubmed: 20574068
Cell Stem Cell. 2011 Jun 3;8(6):688-94
pubmed: 21596650
Cell. 2007 Nov 30;131(5):861-72
pubmed: 18035408
Thromb Haemost. 2015 Apr;113(4):792-805
pubmed: 25518736
Genome Biol. 2016 Feb 16;17:28
pubmed: 26883116
Cell. 2015 Aug 27;162(5):1066-77
pubmed: 26317470
Eur J Immunol. 1998 Oct;28(10):3259-67
pubmed: 9808195
Blood. 2000 May 1;95(9):2943-6
pubmed: 10779443
Cell Stem Cell. 2014 Jul 3;15(1):31-6
pubmed: 24996168
Bioengineered. 2021 Dec;12(1):1517-1529
pubmed: 33926342
Nature. 2019 Aug;572(7770):543-548
pubmed: 31391587
Bioessays. 2004 Sep;26(9):963-77
pubmed: 15351967
Nat Immunol. 2003 Sep;4(9):882-90
pubmed: 12883552
Nucleic Acids Res. 2018 Jul 2;46(W1):W329-W337
pubmed: 29860432
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9648-53
pubmed: 10449748
Ann N Y Acad Sci. 2013 May;1285:26-43
pubmed: 23527602
Elife. 2018 Feb 09;7:
pubmed: 29424691
Science. 2018 Jul 27;361(6400):
pubmed: 29930091
Annu Rev Biochem. 2010;79:707-35
pubmed: 20533885
Cell. 2006 Aug 25;126(4):663-76
pubmed: 16904174
J Clin Immunol. 2018 Jan;38(1):13-27
pubmed: 29086100
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3849-54
pubmed: 11274404
J Biochem. 2003 Sep;134(3):309-13
pubmed: 14561714
J Neurosci. 2003 Oct 1;23(26):8859-66
pubmed: 14523087
Curr Biol. 2015 Mar 16;25(6):804-810
pubmed: 25754639
Pediatr Allergy Immunol. 2010 May;21(3):522-32
pubmed: 20546529
Nat Commun. 2014 Jul 07;5:4330
pubmed: 24999918
Cell Res. 2011 Dec;21(12):1740-4
pubmed: 22105484
Trends Genet. 2013 May;29(5):318-27
pubmed: 23415593
J Exp Med. 1984 Jun 1;159(6):1705-23
pubmed: 6547160
J Allergy Clin Immunol. 2018 Jul;142(1):219-234
pubmed: 29248492
Nat Protoc. 2016 Sep;11(9):1579-85
pubmed: 27490631
Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13781-6
pubmed: 18768795
Nat Rev Clin Oncol. 2020 Aug;17(8):457-474
pubmed: 32303702
Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3854-8
pubmed: 7731995
BMC Bioinformatics. 2022 Feb 15;23(1):72
pubmed: 35168563
BMC Syst Biol. 2010 Apr 13;4:44
pubmed: 20388198
Nucleic Acids Res. 2017 Oct 13;45(18):10350-10368
pubmed: 28977640
Immunodeficiency. 1993;4(1-4):99-108
pubmed: 8167744
Cell. 2020 Dec 23;183(7):1742-1756
pubmed: 33357399
Biochem Cell Biol. 1989 Sep;67(9):503-9
pubmed: 2803729
Surgery. 2009 Jan;145(1):57-68
pubmed: 19081476
Cell. 2007 Jun 29;129(7):1311-23
pubmed: 17604720
J Androl. 2004 Mar-Apr;25(2):200-15
pubmed: 14760006
Blood. 1995 Nov 15;86(10):3797-804
pubmed: 7579347
Nature. 2012 Nov 22;491(7425):603-7
pubmed: 23075850
Nat Biotechnol. 2001 Mar;19(3):242-7
pubmed: 11231557
Cell. 2017 Jan 12;168(1-2):159-171.e14
pubmed: 28041848
Nat Cell Biol. 2004 Nov;6(11):1094-101
pubmed: 15502823
Mol Cell Biol. 2002 Oct;22(19):6871-82
pubmed: 12215544
Cold Spring Harb Perspect Biol. 2011 Feb 01;3(2):
pubmed: 20926517
Br J Haematol. 1998 Jun;101(4):659-65
pubmed: 9674738
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6640-5
pubmed: 10829079
Immunity. 1998 Jul;9(1):81-91
pubmed: 9697838
Mol Cell Biol. 2009 Nov;29(21):5800-12
pubmed: 19704009
Proc Natl Acad Sci U S A. 2003 May 27;100(11):6475-80
pubmed: 12743363
Nature. 2018 Jul;559(7712):61-66
pubmed: 29925947
Haematologica. 2014 Jun;99(6):1069-77
pubmed: 24532043
Elife. 2014 Oct 16;3:
pubmed: 25321392
J Biol Chem. 2007 Nov 23;282(47):34194-203
pubmed: 17890224
Nat Commun. 2018 May 3;9(1):1779
pubmed: 29725003
Immunol Today. 1996 Nov;17(11):496-502
pubmed: 8961624
Gene Ther. 2011 Sep;18(9):874-83
pubmed: 21430784
Sci Data. 2014 Sep 16;1:140031
pubmed: 25977788
Genes Dev. 2010 Nov 1;24(21):2343-64
pubmed: 21041405
EMBO J. 2016 Jun 15;35(12):1254-75
pubmed: 27220849
Transcription. 2013 Sep-Dec;4(5):260-72
pubmed: 24406343
Science. 2019 Mar 8;363(6431):1093-1097
pubmed: 30846599
Biol Open. 2013 Jun 26;2(8):838-44
pubmed: 23951410
Blood. 2005 Feb 15;105(4):1590-7
pubmed: 15494425
Sci Adv. 2020 Apr 15;6(16):eaay6515
pubmed: 32494599
Nucleic Acids Res. 2014 Jul;42(Web Server issue):W361-7
pubmed: 24829458
Nat Rev Mol Cell Biol. 2003 Aug;4(8):605-12
pubmed: 12923522
Curr Protoc Cell Biol. 2007 Sep;Chapter 23:Unit 23.6
pubmed: 18228507
Nat Methods. 2009 May;6(5):359-62
pubmed: 19377485
Nat Methods. 2011 May;8(5):409-12
pubmed: 21460823
Nat Protoc. 2011 Mar;6(3):296-313
pubmed: 21372811
J Biol Chem. 2003 Nov 14;278(46):45672-9
pubmed: 12952985
Nucleic Acids Res. 2022 Jan 7;50(D1):D543-D552
pubmed: 34723319
Blood. 2014 Nov 27;124(23):3409-19
pubmed: 25253772
Nat Rev Immunol. 2010 Mar;10(3):182-92
pubmed: 20182458
Mol Ther. 2004 Oct;10(4):792-8
pubmed: 15451463
Nature. 2019 Sep;573(7772):45-54
pubmed: 31462772
Mol Biol Cell. 1996 Oct;7(10):1559-72
pubmed: 8898362
Nature. 2011 Apr 14;472(7342):221-5
pubmed: 21346760
Science. 2003 Jan 31;299(5607):721-5
pubmed: 12560555
Sci Data. 2019 Nov 22;6(1):278
pubmed: 31757973
Trends Cancer. 2020 Aug;6(8):631-644
pubmed: 32434734
Cell. 2016 Jun 16;165(7):1686-1697
pubmed: 27212236
Cancer Discov. 2013 Nov;3(11):1228-37
pubmed: 24145039
J Immunol. 2014 Jul 1;193(1):150-60
pubmed: 24872192
Nat Rev Genet. 2020 Feb;21(2):71-87
pubmed: 31605096
J Exp Med. 1991 Jun 1;173(6):1501-10
pubmed: 2033371
Stem Cell Reports. 2016 Aug 9;7(2):139-48
pubmed: 27396937