N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO
Open accessAbstract
We report here that fat mass and obesity-associated protein (FTO) has efficient oxidative demethylation activity targeting the abundant N6-methyladenosine (m(6)A) residues in RNA in vitro. FTO knockdown with siRNA led to increased amounts of m(6)A in mRNA, whereas overexpression of FTO resulted in decreased amounts of m(6)A in human cells. We further show the partial colocalization of FTO with nuclear speckles, which supports the notion that m(6)A in nuclear RNA is a major physiological substrate of FTO.
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The m6A modification can be removed by erasers, mainly FTO and ALKBH5.
“The m6A modification can be removed by erasers, mainly FTO and ALKBH5 [24,25].”
From IMPlications of IMP2 in RNA Biology and Disease (2025) · cites this paper as [24]
Evidence points to an oncogenic role of FTO in AML.
“Although evidence points to an oncogenic role of FTO in AML 15 ,”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [15]
D2HG can inhibit the N6-methyladenosine (m6A) RNA demethylase fat mass and obesity associated protein (FTO), another α-KG-dependent dioxygenase.
“In addition to TET enzymes, D2HG can inhibit the N6-methyladenosine (m6A) RNA demethylase fat mass and obesity associated protein (FTO), another α -KG-dependent dioxygenase 15 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [15]
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Self-citationZc3h13 Regulates Nuclear RNA m6A Methylation and Mouse Embryonic Stem Cell Self-Renewal
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“Whether and how WTAP regulates alternative splicing in an m6A-dependent manner have yet to be systematically explored. m6A erasers in mammals FTO is the first identified demethylase that oxidatively reverses m6A to adenosine inmRNA (Jia et al. 2011).”
InfluentialSelf-citationRNA m6A methylation regulates the ultraviolet-induced DNA damage response
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“Furthermore, mutations in one of the human demethylase genes is associated with a phenotype (overweight) (Jia et al. 2011; Zheng et al. 2013).”
Backgroundm6A RNA methylation: from mechanisms to therapeutic potential
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Self-citationN 6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein
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Self-citationDifferential m6A, m6Am, and m1A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm
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“This modification is reversible 3 , and its biological effects are mostly mediated through “writer,” “eraser,” and “reader” proteins 1,2 .”
Self-citationTargeting FTO suppresses cancer stem cell maintenance and immune evasion
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Self-citationThe m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation
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Self-citationThe epitranscriptome beyond m6A
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Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain
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Self-citationTranscriptome-wide mapping reveals reversible and dynamic N1-methyladenosine methylome
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Self-citationMeclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5
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InfluentialThe RNA modification landscape in human disease
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Self-citationN6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis
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Self-citationm6A modulates neuronal functions and sex determination in Drosophila
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m6A facilitates hippocampus-dependent learning and memory through YTHDF1
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Self-citation
- Authors
- Jia, G., Fu, Y., Zhao, X., Dai, Q., Zheng, G., Yang, Y., Yi, C., Lindahl, T., Pan, T., Yang, Y.-G., & He, C.
- Affiliations
- University of Chicago (US)
- Chinese Academy of Sciences (CN)
- Cancer Research UK (GB)
- Corresponding author
- He, Chuan
- Venue
- Nature Chemical Biology
- Published
- 2011-10-16
- Volume
- 7
- Issue
- 12
- Pages
- 885-887
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC3218240
- OpenAlex
- W2071930821
- Cited by
- 4,106
- References
- 27
- Citations by year
- 2026: 272 · 2025: 416 · 2024: 473 · 2023: 489 · 2022: 546 · 2021: 544 · 2020: 341 · 2019: 217 · 2018: 218 · 2017: 159 · 2016: 109 · 2015: 107 · 2014: 94 · 2013: 67 · 2012: 45
- FWCI
- 26.98
- Type
- journal article
- Language
- en
- Update notices
- erratum (2012-11-26)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (GM071440, R01GM071440, R01GM088599, GM088599)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- N6-methyladenosine, m6A demethylation, FTO, nuclear RNA, RNA modification, oxidative demethylation, nuclear speckles, obesity, RNA metabolism
- MeSH terms
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Adenosine, Cell Nucleus, HeLa Cells, Humans, Methylation, Obesity, Oxidation-Reduction, Proteins, RNA, Messenger, Substrate Specificity
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