Differential m                         6                         A, m                         6                         A                         m                         , and m                         1                         A 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 m ⁶ A, m ⁶ A _m , and m ¹ A 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^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

648 Scopus citations

Abstract

FTO, the first RNA demethylase discovered, mediates the demethylation of internal N ⁶ -methyladenosine (m ⁶ A) and N ⁶ , 2-O-dimethyladenosine (m ⁶ A _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 m ⁶ A and cap m ⁶ A _m in mRNA, internal m ⁶ A in U6 RNA, internal and cap m ⁶ A _m in snRNAs, and N ¹ -methyladenosine (m ¹ A) in tRNA. FTO-mediated demethylation has a greater effect on the transcript levels of mRNAs possessing internal m ⁶ A than the ones with cap m ⁶ A _m in the tested cells. We also show that FTO can directly repress translation by catalyzing m ¹ A tRNA demethylation. Collectively, FTO-mediated RNA demethylation occurs to m ⁶ A and m ⁶ A _m in mRNA and snRNA as well as m ¹ A in tRNA. Wei et al. show that FTO mediates internal m ⁶ A and cap m ⁶ A _m demethylation of polyadenylated RNA with differential substrate preferences in the nucleus versus the cytoplasm, in which the internal m ⁶ A demethylation correlates with transcript-level changes. FTO also affects snRNA m ⁶ A and m ⁶ A _m levels and mediates tRNA m ¹ A demethylation.

Original language	English (US)
Pages (from-to)	973-985.e5
Journal	Molecular cell
Volume	71
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2018.08.011
State	Published - Sep 20 2018

Funding

This work is supported by the U.S. National Insititutes of Health ( GM071440 and HG008935 to C.H., and CA214965 to J.C.) and the National Basic Research Program of China ( 2014CB964900 to G.J.). The Mass Spectrometry Facility of the University of Chicago is funded by the U.S. National Science Foundation ( CHE-1048528 ). The University of Chicago Cancer Center is supported by the U.S. National Institutes of Health CA014599 . C.H. is an investigator of the Howard Hughes Medical Institute. This work is supported by the U.S. National Insititutes of Health (GM071440 and HG008935 to C.H., and CA214965 to J.C.) and the National Basic Research Program of China (2014CB964900 to G.J.). The Mass Spectrometry Facility of the University of Chicago is funded by the U.S. National Science Foundation (CHE-1048528). The University of Chicago Cancer Center is supported by the U.S. National Institutes of Health CA014599. C.H. is an investigator of the Howard Hughes Medical Institute.

Keywords

FTO
cap m A
cytoplasmic demethylation
m A
nuclear m A demethylation
snRNA demethylation
tRNA m A demethylation
translation regulation

ASJC Scopus subject areas

Molecular Biology
Cell Biology

Access to Document

10.1016/j.molcel.2018.08.011

Cite this

Wei, J., Liu, F., Lu, Z., Fei, Q., Ai, Y., He, P. C., Shi, H., Cui, X., Su, R., Klungland, A., Jia, G., Chen, J., & He, C. (2018). Differential m ⁶ A, m ⁶ A _m , and m ¹ A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm. Molecular cell, 71(6), 973-985.e5. https://doi.org/10.1016/j.molcel.2018.08.011

Wei, Jiangbo ; Liu, Fange ; Lu, Zhike et al. / Differential m ⁶ A, m ⁶ A _m , and m ¹ A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm. In: Molecular cell. 2018 ; Vol. 71, No. 6. pp. 973-985.e5.

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title = "Differential m 6 A, m 6 A m , and m 1 A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm",

abstract = " FTO, the first RNA demethylase discovered, mediates the demethylation of internal N 6 -methyladenosine (m 6 A) and N 6 , 2-O-dimethyladenosine (m 6 A 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 m 6 A and cap m 6 A m in mRNA, internal m 6 A in U6 RNA, internal and cap m 6 A m in snRNAs, and N 1 -methyladenosine (m 1 A) in tRNA. FTO-mediated demethylation has a greater effect on the transcript levels of mRNAs possessing internal m 6 A than the ones with cap m 6 A m in the tested cells. We also show that FTO can directly repress translation by catalyzing m 1 A tRNA demethylation. Collectively, FTO-mediated RNA demethylation occurs to m 6 A and m 6 A m in mRNA and snRNA as well as m 1 A in tRNA. Wei et al. show that FTO mediates internal m 6 A and cap m 6 A m demethylation of polyadenylated RNA with differential substrate preferences in the nucleus versus the cytoplasm, in which the internal m 6 A demethylation correlates with transcript-level changes. FTO also affects snRNA m 6 A and m 6 A m levels and mediates tRNA m 1 A demethylation.",

keywords = "FTO, cap m A, cytoplasmic demethylation, m A, nuclear m A demethylation, snRNA demethylation, tRNA m A demethylation, translation regulation",

author = "Jiangbo Wei and Fange Liu and Zhike Lu and Qili Fei and Yuxi Ai and He, \{P. Cody\} and Hailing Shi and Xiaolong Cui and Rui Su and Arne Klungland and Guifang Jia and Jianjun Chen and Chuan He",

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Wei, J, Liu, F, Lu, Z, Fei, Q, Ai, Y, He, PC, Shi, H, Cui, X, Su, R, Klungland, A, Jia, G, Chen, J & He, C 2018, 'Differential m ⁶ A, m ⁶ A _m , and m ¹ A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm', Molecular cell, vol. 71, no. 6, pp. 973-985.e5. https://doi.org/10.1016/j.molcel.2018.08.011

Differential m ⁶ A, m ⁶ A _m , and m ¹ A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm. / Wei, Jiangbo; Liu, Fange; Lu, Zhike et al.
In: Molecular cell, Vol. 71, No. 6, 20.09.2018, p. 973-985.e5.

Research output: Contribution to journal › Article › peer-review

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T1 - Differential m 6 A, m 6 A m , and m 1 A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm

AU - Wei, Jiangbo

AU - Liu, Fange

AU - Lu, Zhike

AU - Fei, Qili

AU - Ai, Yuxi

AU - He, P. Cody

AU - Shi, Hailing

AU - Cui, Xiaolong

AU - Su, Rui

AU - Klungland, Arne

AU - Jia, Guifang

AU - Chen, Jianjun

AU - He, Chuan

PY - 2018/9/20

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N2 - FTO, the first RNA demethylase discovered, mediates the demethylation of internal N 6 -methyladenosine (m 6 A) and N 6 , 2-O-dimethyladenosine (m 6 A 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 m 6 A and cap m 6 A m in mRNA, internal m 6 A in U6 RNA, internal and cap m 6 A m in snRNAs, and N 1 -methyladenosine (m 1 A) in tRNA. FTO-mediated demethylation has a greater effect on the transcript levels of mRNAs possessing internal m 6 A than the ones with cap m 6 A m in the tested cells. We also show that FTO can directly repress translation by catalyzing m 1 A tRNA demethylation. Collectively, FTO-mediated RNA demethylation occurs to m 6 A and m 6 A m in mRNA and snRNA as well as m 1 A in tRNA. Wei et al. show that FTO mediates internal m 6 A and cap m 6 A m demethylation of polyadenylated RNA with differential substrate preferences in the nucleus versus the cytoplasm, in which the internal m 6 A demethylation correlates with transcript-level changes. FTO also affects snRNA m 6 A and m 6 A m levels and mediates tRNA m 1 A demethylation.

AB - FTO, the first RNA demethylase discovered, mediates the demethylation of internal N 6 -methyladenosine (m 6 A) and N 6 , 2-O-dimethyladenosine (m 6 A 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 m 6 A and cap m 6 A m in mRNA, internal m 6 A in U6 RNA, internal and cap m 6 A m in snRNAs, and N 1 -methyladenosine (m 1 A) in tRNA. FTO-mediated demethylation has a greater effect on the transcript levels of mRNAs possessing internal m 6 A than the ones with cap m 6 A m in the tested cells. We also show that FTO can directly repress translation by catalyzing m 1 A tRNA demethylation. Collectively, FTO-mediated RNA demethylation occurs to m 6 A and m 6 A m in mRNA and snRNA as well as m 1 A in tRNA. Wei et al. show that FTO mediates internal m 6 A and cap m 6 A m demethylation of polyadenylated RNA with differential substrate preferences in the nucleus versus the cytoplasm, in which the internal m 6 A demethylation correlates with transcript-level changes. FTO also affects snRNA m 6 A and m 6 A m levels and mediates tRNA m 1 A demethylation.

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KW - m A

KW - nuclear m A demethylation

KW - snRNA demethylation

KW - tRNA m A demethylation

KW - translation regulation

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Wei J, Liu F, Lu Z, Fei Q, Ai Y, He PC et al. Differential m ⁶ A, m ⁶ A _m , and m ¹ A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm. Molecular cell. 2018 Sep 20;71(6):973-985.e5. doi: 10.1016/j.molcel.2018.08.011