N6-methyladenosine demethylase FTO targets pre-mRNAs and
regulates alternative splicing and 3'-end processing

J 2017

N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3'-end processing

BARTOŠOVIČ, Marek, Helena COVELO MOLARES, Pavlína GREGOROVÁ, Dominika HROŠŠOVÁ, G. KUDLA et. al.

Základní údaje

Originální název

N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3'-end processing

Autoři

BARTOŠOVIČ, Marek (703 Slovensko, domácí), Helena COVELO MOLARES (724 Španělsko, domácí), Pavlína GREGOROVÁ (703 Slovensko, domácí), Dominika HROŠŠOVÁ (703 Slovensko, domácí), G. KUDLA (826 Velká Británie a Severní Irsko) a Štěpánka VAŇÁČOVÁ (203 Česká republika, garant, domácí)

Vydání

Nucleic Acids Research, Oxford, Oxford University Press, 2017, 0305-1048

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 11.561

Kód RIV

RIV/00216224:14740/17:00095526

Organizační jednotka

Středoevropský technologický institut

DOI

http://dx.doi.org/10.1093/nar/gkx778

UT WoS

000414552300037

Klíčová slova anglicky

EMBRYONIC STEM-CELLS; BLOCKED 5' TERMINI; SEX DETERMINATION; COMPREHENSIVE ANALYSIS; NUCLEAR-RNA; METHYLATION; DROSOPHILA; REVEALS; OBESITY; N-6-METHYLADENOSINE

Štítky

OA, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 28. 2. 2018 09:11, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

N6-methyladenosine (m(6)A) is the most abundant base modification found in messenger RNAs (mRNAs). The discovery of FTO as the first m6A mRNA demethylase established the concept of reversible RNA modification. Here, we present a comprehensive transcriptome-wide analysis of RNA demethylation and uncover FTO as a potent regulator of nuclear mRNA processing events such as alternative splicing and 3' end mRNA processing. We show that FTO binds preferentially to pre-mRNAs in intronic regions, in the proximity of alternatively spliced (AS) exons and poly(A) sites. FTO knockout (KO) results in substantial changes in pre-mRNA splicing with prevalence of exon skipping events. The alternative splicing effects of FTO KO anti-correlate with METTL3 knockdown suggesting the involvement of m(6)A. Besides, deletion of intronic region that contains m(6)A-linked DRACH motifs partially rescues the FTO KO phenotype in a reporter system. All together, we demonstrate that the splicing effects of FTO are dependent on the catalytic activity in vivo and are mediated by m(6)A. Our results reveal for the first time the dynamic connection between FTO RNA binding and demethylation activity that influences several mRNA processing events.

Návaznosti

GAP305/11/1095, projekt VaV

Název: Funkční a biochemická charakterizace proteinu Dis3L2, třetího lidského homologu hlavní kvasinkové exosomové nukleázy Dis3p

Investor: Grantová agentura ČR, Funkční a biochemická charakterizace proteinu Dis3L2, třetího lidského homologu hlavní kvasinkové exosomové nukleázy Dis3p

GA14-25884S, projekt VaV

Název: Charakterizace substrátového repertoáru RNA lidské demetylázy FTO

Investor: Grantová agentura ČR, Charakterizace substrátového repertoáru RNA lidské demetylázy FTO

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

Citovat

BARTOŠOVIČ, Marek, Helena COVELO MOLARES, Pavlína GREGOROVÁ, Dominika HROŠŠOVÁ, G. KUDLA a Štěpánka VAŇÁČOVÁ. N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3'-end processing. Nucleic Acids Research. Oxford: Oxford University Press, 2017, roč. 45, č. 19, s. 11356-11370. ISSN 0305-1048. Dostupné z: https://dx.doi.org/10.1093/nar/gkx778.

@article{1409373,
   author = {Bartošovič, Marek and Covelo Molares, Helena and Gregorová, Pavlína and Hroššová, Dominika and Kudla, G. and Vaňáčová, Štěpánka},
   article_location = {Oxford},
   article_number = {19},
   doi = {http://dx.doi.org/10.1093/nar/gkx778},
   keywords = {EMBRYONIC STEM-CELLS; BLOCKED 5' TERMINI; SEX DETERMINATION; COMPREHENSIVE ANALYSIS; NUCLEAR-RNA; METHYLATION; DROSOPHILA; REVEALS; OBESITY; N-6-METHYLADENOSINE},
   language = {eng},
   issn = {0305-1048},
   journal = {Nucleic Acids Research},
   title = {N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3'-end processing},
   url = {https://academic.oup.com/nar/article/45/19/11356/4097621},
   volume = {45},
   year = {2017}
}

TY  - JOUR
ID  - 1409373
AU  - Bartošovič, Marek - Covelo Molares, Helena - Gregorová, Pavlína - Hroššová, Dominika - Kudla, G. - Vaňáčová, Štěpánka
PY  - 2017
TI  - N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3'-end processing
JF  - Nucleic Acids Research
VL  - 45
IS  - 19
SP  - 11356-11370
EP  - 11356-11370
PB  - Oxford University Press
SN  - 03051048
KW  - EMBRYONIC STEM-CELLS
KW  - BLOCKED 5' TERMINI
KW  - SEX DETERMINATION
KW  - COMPREHENSIVE ANALYSIS
KW  - NUCLEAR-RNA
KW  - METHYLATION
KW  - DROSOPHILA
KW  - REVEALS
KW  - OBESITY
KW  - N-6-METHYLADENOSINE
UR  - https://academic.oup.com/nar/article/45/19/11356/4097621
L2  - https://academic.oup.com/nar/article/45/19/11356/4097621
N2  - N6-methyladenosine (m(6)A) is the most abundant base modification found in messenger RNAs (mRNAs). The discovery of FTO as the first m6A mRNA demethylase established the concept of reversible RNA modification. Here, we present a comprehensive transcriptome-wide analysis of RNA demethylation and uncover FTO as a potent regulator of nuclear mRNA processing events such as alternative splicing and 3' end mRNA processing. We show that FTO binds preferentially to pre-mRNAs in intronic regions, in the proximity of alternatively spliced (AS) exons and poly(A) sites. FTO knockout (KO) results in substantial changes in pre-mRNA splicing with prevalence of exon skipping events. The alternative splicing effects of FTO KO anti-correlate with METTL3 knockdown suggesting the involvement of m(6)A. Besides, deletion of intronic region that contains m(6)A-linked DRACH motifs partially rescues the FTO KO phenotype in a reporter system. All together, we demonstrate that the splicing effects of FTO are dependent on the catalytic activity in vivo and are mediated by m(6)A. Our results reveal for the first time the dynamic connection between FTO RNA binding and demethylation activity that influences several mRNA processing events.
ER  -

BARTOŠOVIČ, Marek, Helena COVELO MOLARES, Pavlína GREGOROVÁ, Dominika HROŠŠOVÁ, G. KUDLA a Štěpánka VAŇÁČOVÁ. N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3'-end processing. \textit{Nucleic Acids Research}. Oxford: Oxford University Press, 2017, roč.~45, č.~19, s.~11356-11370. ISSN~0305-1048. Dostupné z: https://dx.doi.org/10.1093/nar/gkx778.

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