Differential m6A, m6Am, and m1A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm

Jiangbo Wei; Fange Liu; Zhike Lu; Qili Fei; Yuxi Ai; P Cody He; Hailing Shi; Xiaolong Cui; Rui Su; Arne Klungland; Guifang Jia; Jianjun Chen; Chuan He

doi:10.1016/j.molcel.2018.08.011

Differential m⁶A, m⁶A_m, and m¹A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm

Mol Cell. 2018 Sep 20;71(6):973-985.e5. doi: 10.1016/j.molcel.2018.08.011. Epub 2018 Sep 6.

Authors

Jiangbo Wei¹, Fange Liu¹, Zhike Lu², Qili Fei¹, Yuxi Ai¹, P Cody He¹, Hailing Shi¹, Xiaolong Cui¹, Rui Su³, Arne Klungland⁴, Guifang Jia⁵, Jianjun Chen³, Chuan He⁶

Affiliations

¹ Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57 Street, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, 929 East 57 Street, Chicago, IL 60637, USA.
² Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57 Street, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, 929 East 57 Street, Chicago, IL 60637, USA; Institute of Natural Sciences, Westlake Institute for Advanced Study, Westlake University, 18 Shilongshan Road, Hangzhou 310064, China.
³ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
⁴ Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet, Norway Institute of Basic Medical Sciences, University of Oslo, PO Box 1018 Blindern, 0315 Oslo, Norway.
⁵ Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
⁶ Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57 Street, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, 929 East 57 Street, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.

Abstract

FTO, the first RNA demethylase discovered, mediates the demethylation of internal N⁶-methyladenosine (m⁶A) and N⁶, 2-O-dimethyladenosine (m⁶A_m) at the +1 position from the 5' cap in mRNA. Here we demonstrate that the cellular distribution of FTO is distinct among different cell lines, affecting the access of FTO to different RNA substrates. We find that FTO binds multiple RNA species, including mRNA, snRNA, and tRNA, and can demethylate internal m⁶A and cap m⁶A_m in mRNA, internal m⁶A in U6 RNA, internal and cap m⁶A_m in snRNAs, and N¹-methyladenosine (m¹A) in tRNA. FTO-mediated demethylation has a greater effect on the transcript levels of mRNAs possessing internal m⁶A than the ones with cap m⁶A_m in the tested cells. We also show that FTO can directly repress translation by catalyzing m¹A tRNA demethylation. Collectively, FTO-mediated RNA demethylation occurs to m⁶A and m⁶A_m in mRNA and snRNA as well as m¹A in tRNA.

Keywords: FTO; cap m(6)A(m); cytoplasmic demethylation; m(6)A; nuclear m(6)A demethylation; snRNA demethylation; tRNA m(1)A demethylation; translation regulation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

3T3-L1 Cells
Adenosine / analogs & derivatives*
Adenosine / metabolism
Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics*
Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism
Alpha-Ketoglutarate-Dependent Dioxygenase FTO / physiology*
Animals
Cell Nucleus
Cytoplasm
Demethylation
Gene Expression / genetics
HEK293 Cells
HeLa Cells
Humans
Methylation
Mice
RNA Processing, Post-Transcriptional / physiology
RNA, Messenger / metabolism
RNA, Small Nuclear / metabolism
RNA, Transfer / metabolism

Substances

RNA, Messenger
RNA, Small Nuclear
U6 small nuclear RNA
RNA, Transfer
N-methyladenosine
FTO protein, mouse
Alpha-Ketoglutarate-Dependent Dioxygenase FTO
Adenosine

Abstract

Publication types

MeSH terms

Substances

Grants and funding