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.

Basic information

Original name

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

Authors

BARTOŠOVIČ, Marek (703 Slovakia, belonging to the institution), Helena COVELO MOLARES (724 Spain, belonging to the institution), Pavlína GREGOROVÁ (703 Slovakia, belonging to the institution), Dominika HROŠŠOVÁ (703 Slovakia, belonging to the institution), G. KUDLA (826 United Kingdom of Great Britain and Northern Ireland) and Štěpánka VAŇÁČOVÁ (203 Czech Republic, guarantor, belonging to the institution)

Edition

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

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 11.561

RIV identification code

RIV/00216224:14740/17:00095526

Organization unit

Central European Institute of Technology

DOI

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

UT WoS

000414552300037

Keywords in English

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

Abstract

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.

Links

GAP305/11/1095, research and development project

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

Investor: Czech Science Foundation, Functional and biochemical characterization of Dis3L2, the third mammalian homolog of the key yeast exosome nuclease Dis3p

GA14-25884S, research and development project

Name: Charakterizace substrátového repertoáru RNA lidské demetylázy FTO

Investor: Czech Science Foundation

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

Citovat

BARTOŠOVIČ, Marek, Helena COVELO MOLARES, Pavlína GREGOROVÁ, Dominika HROŠŠOVÁ, G. KUDLA and 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, vol. 45, No 19, p. 11356-11370. ISSN 0305-1048. Available from: 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 and 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, vol.~45, No~19, p.~11356-11370. ISSN~0305-1048. Available from: https://dx.doi.org/10.1093/nar/gkx778.

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