Intronic tRNAs of mitochondrial origin regulate constitutive and alternative splicing.
Alternative splicing
Constitutive splicing
Intronic splicing enhancer (ISE)
Mitochondrial tRNA
Splicing
Splicing regulatory element
nimtRNA
numtDNA
tRNA
tRNA-lookalikes
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
08 12 2020
08 12 2020
Historique:
received:
24
03
2020
accepted:
09
11
2020
entrez:
9
12
2020
pubmed:
10
12
2020
medline:
1
12
2021
Statut:
epublish
Résumé
The presence of nuclear mitochondrial DNA (numtDNA) has been reported within several nuclear genomes. Next to mitochondrial protein-coding genes, numtDNA sequences also encode for mitochondrial tRNA genes. However, the biological roles of numtDNA remain elusive. Employing in silico analysis, we identify 281 mitochondrial tRNA homologs in the human genome, which we term nimtRNAs (nuclear intronic mitochondrial-derived tRNAs), being contained within introns of 76 nuclear host genes. Despite base changes in nimtRNAs when compared to their mtRNA homologs, a canonical tRNA cloverleaf structure is maintained. To address potential functions of intronic nimtRNAs, we insert them into introns of constitutive and alternative splicing reporters and demonstrate that nimtRNAs promote pre-mRNA splicing, dependent on the number and positioning of nimtRNA genes and splice site recognition efficiency. A mutational analysis reveals that the nimtRNA cloverleaf structure is required for the observed splicing increase. Utilizing a CRISPR/Cas9 approach, we show that a partial deletion of a single endogenous nimtRNA We propose that nimtRNAs, along with associated protein factors, can act as a novel class of intronic splicing regulatory elements in the human genome by participating in the regulation of splicing.
Sections du résumé
BACKGROUND
The presence of nuclear mitochondrial DNA (numtDNA) has been reported within several nuclear genomes. Next to mitochondrial protein-coding genes, numtDNA sequences also encode for mitochondrial tRNA genes. However, the biological roles of numtDNA remain elusive.
RESULTS
Employing in silico analysis, we identify 281 mitochondrial tRNA homologs in the human genome, which we term nimtRNAs (nuclear intronic mitochondrial-derived tRNAs), being contained within introns of 76 nuclear host genes. Despite base changes in nimtRNAs when compared to their mtRNA homologs, a canonical tRNA cloverleaf structure is maintained. To address potential functions of intronic nimtRNAs, we insert them into introns of constitutive and alternative splicing reporters and demonstrate that nimtRNAs promote pre-mRNA splicing, dependent on the number and positioning of nimtRNA genes and splice site recognition efficiency. A mutational analysis reveals that the nimtRNA cloverleaf structure is required for the observed splicing increase. Utilizing a CRISPR/Cas9 approach, we show that a partial deletion of a single endogenous nimtRNA
CONCLUSIONS
We propose that nimtRNAs, along with associated protein factors, can act as a novel class of intronic splicing regulatory elements in the human genome by participating in the regulation of splicing.
Identifiants
pubmed: 33292386
doi: 10.1186/s13059-020-02199-6
pii: 10.1186/s13059-020-02199-6
pmc: PMC7722341
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
DNA-Binding Proteins
0
KHDRBS1 protein, human
0
PPFIBP1 protein, human
0
RNA Splice Sites
0
RNA, Messenger
0
RNA-Binding Proteins
0
RNA, Transfer
9014-25-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
299Références
Biol Direct. 2010 Jun 16;5:39
pubmed: 20553583
Nucleic Acids Res. 1997 Mar 1;25(5):955-64
pubmed: 9023104
Int Rev Cytol. 1992;141:233-357
pubmed: 1452433
Nature. 2013 Jul 11;499(7457):172-7
pubmed: 23846655
Nucleic Acids Res. 2013 Sep;41(17):8144-65
pubmed: 23861442
Biochimie. 2002 Aug;84(8):775-90
pubmed: 12457565
Nucleic Acids Res. 2014 Apr;42(7):4640-51
pubmed: 24464992
Endocr Relat Cancer. 2011 Jul 01;18(4):R91-R102
pubmed: 21565971
Trends Genet. 2019 Jan;35(1):68-87
pubmed: 30466729
Methods. 2020 Jun 1;178:11-18
pubmed: 31563541
Nucleic Acids Res. 2008 Mar;36(5):1450-63
pubmed: 18203748
Nucleic Acids Res. 2014 Dec 16;42(22):e168
pubmed: 25300484
Curr Protoc Bioinformatics. 2016 Jun 20;54:1.30.1-1.30.33
pubmed: 27322403
Cold Spring Harb Protoc. 2013 Feb 01;2013(2):156-63
pubmed: 23378656
Mol Biol (Mosk). 2010 May-Jun;44(3):405-17
pubmed: 20608164
Nat Methods. 2016 Jun;13(6):508-14
pubmed: 27018577
Nature. 1981 Apr 9;290(5806):457-65
pubmed: 7219534
Mol Cell Biol. 1997 Oct;17(10):5707-18
pubmed: 9315629
Genome Res. 2002 Jun;12(6):885-93
pubmed: 12045142
Chem Rev. 2007 Aug;107(8):3407-30
pubmed: 17645315
RNA Biol. 2015;12(4):375-80
pubmed: 25849196
Cancer Res. 2003 Nov 1;63(21):7507-14
pubmed: 14612552
Nucleic Acids Res. 2016 Jan 4;44(D1):D7-19
pubmed: 26615191
Biomed Rep. 2015 Mar;3(2):152-158
pubmed: 25798239
Nucleic Acids Res. 2017 Apr 20;45(7):4202-4216
pubmed: 28039323
RNA. 2013 Jan;19(1):96-102
pubmed: 23175589
PLoS Genet. 2011 Oct;7(10):e1002330
pubmed: 22028668
Nucleic Acids Res. 2018 Jan 4;46(D1):D794-D801
pubmed: 29126249
Mol Cell Biol. 2005 Apr;25(8):3295-304
pubmed: 15798213
Nucleic Acids Res. 2012 Apr;40(7):2833-45
pubmed: 22139921
J Cell Biol. 2006 Apr 24;173(2):207-18
pubmed: 16618814
Nucleic Acids Res. 2018 Jul 2;46(W1):W242-W245
pubmed: 29762716
Nature. 2012 Sep 6;489(7414):57-74
pubmed: 22955616
Cell. 2009 Feb 20;136(4):701-18
pubmed: 19239890
Hum Mutat. 2004 Feb;23(2):125-33
pubmed: 14722916
Mol Biol Evol. 2001 Sep;18(9):1833-7
pubmed: 11504863
Nucleic Acids Res. 1980 Nov 25;8(22):5213-22
pubmed: 6906662
Methods Enzymol. 2015;558:235-278
pubmed: 26068744
Science. 1991 Mar 15;251(4999):1351-5
pubmed: 1900642
Nucleic Acids Res. 2019 Jan 8;47(D1):D442-D450
pubmed: 30395289
Trends Biochem Sci. 2013 Jun;38(6):283-91
pubmed: 23632312
Mol Cell. 2018 Oct 4;72(1):99-111.e5
pubmed: 30220559
PLoS One. 2011 Apr 29;6(4):e19152
pubmed: 21559454
Genome Res. 2002 Jun;12(6):996-1006
pubmed: 12045153
Nat Methods. 2014 Aug;11(8):783-784
pubmed: 25075903
Annu Rev Genet. 2011;45:299-329
pubmed: 21910628
Genome Res. 2018 Dec;28(12):1826-1840
pubmed: 30355602
Nucleic Acids Res. 2014;42(16):10681-97
pubmed: 25147205
Nucleic Acids Res. 2018 Jan 4;46(D1):D754-D761
pubmed: 29155950
Database (Oxford). 2016 Apr 07;2016:
pubmed: 27055826
Nucleic Acids Res. 2014 Jul;42(Web Server issue):W361-7
pubmed: 24829458
Nucleic Acids Res. 2019 Jan 8;47(D1):D766-D773
pubmed: 30357393
RNA. 2020 Oct;26(10):1389-1399
pubmed: 32522889
Cell. 2011 Aug 19;146(4):645-58
pubmed: 21854988
Int J Mol Sci. 2013 Nov 20;14(11):22906-32
pubmed: 24264039
J Theor Biol. 2011 Jan 21;269(1):287-96
pubmed: 21073883
Nucleic Acids Res. 2003 Feb 1;31(3):869-77
pubmed: 12560482
Nucleic Acids Res. 2016 Feb 18;44(3):1342-53
pubmed: 26657638
Mol Cell Biol. 2005 Jul;25(13):5396-403
pubmed: 15964797
Biochim Biophys Acta. 2012 Sep-Oct;1819(9-10):1017-26
pubmed: 22137969
J Theor Biol. 2012 Apr 7;298:51-76
pubmed: 22244915
RNA Biol. 2010 Jan-Feb;7(1):56-64
pubmed: 19946215
Mol Cell. 2018 Sep 20;71(6):1012-1026.e3
pubmed: 30174293
Hum Mutat. 2005 Feb;25(2):207-21
pubmed: 15643617
J Mol Evol. 2003 Sep;57(3):343-54
pubmed: 14629044
Nucleic Acids Res. 2012 Oct;40(18):9073-88
pubmed: 22761406
Genomics. 2002 Jul;80(1):71-7
pubmed: 12079285
Mol Biol Evol. 2016 Jul;33(7):1870-4
pubmed: 27004904
Nucleic Acids Res. 2011 Jan;39(Database issue):D301-8
pubmed: 21036867
Mol Cell Biol. 2006 Apr;26(7):2540-9
pubmed: 16537900
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Mol Biol Evol. 2003 Oct;20(10):1659-68
pubmed: 12885966
Front Genet. 2014 Oct 08;5:344
pubmed: 25339973
PLoS Comput Biol. 2009 Sep;5(9):e1000502
pubmed: 19750212
RNA. 2014 Dec;20(12):1929-43
pubmed: 25344396
Nucleic Acids Res. 2004 Mar 19;32(5):1792-7
pubmed: 15034147
Mol Biol Evol. 2007 Jan;24(1):13-8
pubmed: 17056643
Curr Opin Genet Dev. 2011 Aug;21(4):373-9
pubmed: 21530232
Bioinformatics. 2013 Nov 15;29(22):2933-5
pubmed: 24008419
RNA. 2012 May;18(5):900-14
pubmed: 22450757