FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis

By Xu Zhao, Ying Yang, Bao-Fa Sun, Yue Shi, Xin Yang, Wen Xiao, Ya-Juan Hao, X. Ping, Yu-Sheng Chen, Wen-Jia Wang and 17 more. Cell Research, 2014

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The role of Fat Mass and Obesity-associated protein (FTO) and its substrate N6-methyladenosine (m6A) in mRNA processing and adipogenesis remains largely unknown. We show that FTO expression and m6A levels are inversely correlated during adipogenesis. FTO depletion blocks differentiation and only catalytically active FTO restores adipogenesis. Transcriptome analyses in combination with m6A-seq revealed that gene expression and mRNA splicing of grouped genes are regulated by FTO. M6A is enriched in exonic regions flanking 5′- and 3′-splice sites, spatially overlapping with mRNA splicing regulatory serine/arginine-rich (SR) protein exonic splicing enhancer binding regions. Enhanced levels of m6A in response to FTO depletion promotes the RNA binding ability of SRSF2 protein, leading to increased inclusion of target exons. FTO controls exonic splicing of adipogenic regulatory factor RUNX1T1 by regulating m6A levels around splice sites and thereby modulates differentiation. These findings provide compelling evidence that FTO-dependent m6A demethylation functions as a novel regulatory mechanism of RNA processing and plays a critical role in the regulation of adipogenesis.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/206ad7a201c6fd6fc827f01b18a31162da314cf8

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Citations in the corpus

Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “So far, all functionally relevant reports of FTO have been consistent with internal m6A but not cap m(6)Am in mRNA being the relevant substrate, including but not limited to facilitating the 3T3-L1 cell differentiation (Zhao et al., 2014); responding to heat shock (Zhou et al.”
Critical Roles of N6-Methyladenosine (m6A) in Cancer and Virus Infection (2020, background): “Furthermore, FTO-dependent demethylation of m6A has been shown to control alternative splicing of Runt-related transcription factor 1 (RUNX1T1) by regulating the serine/arginine-rich splicing factor 2 (SRSF2) [58].”
The role of m6A RNA methylation in cancer metabolism (2022, background): “As a reversible step of m6A methylation, demethylase FTO can regulate fat production and energy homeostasis [25].”
Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “Our previous report demonstrated that enhanced levels of m(6)A in response to FTO depletion in mouse pre-adipocytes promote the RNA binding ability of serine- and arginine-rich splicing factor 2 (SRSF2), leading to increased inclusion of target exons.(12) A recent study in the human 293T cell line r”
Functions of N6-methyladenosine and its role in cancer (2019, background): “FTO not only controls mRNA splicing by inhibiting SRSF2 binding at splice sites [65], but also regulates Fig.”
Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia (2019, background): “, 2012), as well as coding regions (Rana and Tuck, 1990), which is critical for the regulation of mRNA stability (Huang et al., 2018; Wang et al., 2014a; Zhao et al., 2014), splicing (Xiao et al.”
METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6‐methyladenosine‐dependent primary MicroRNA processing (2017, background): “Previous studies suggested that m(6)A modification might be implicated in the splicing process of mRNAs.((11)) Recently, Alarcon and colleagues demonstrated that m(6)A modification could mark primiRNAs for processing by recognizing DGCR8 in a manner dependent on METTL3/m(6)A, suggesting that altered”
Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis (2017, background): “Notably, reanalysis of m6A crosslinking and immunoprecipitation (CLIP) data (Zhao et al., 2014) and m6A immunoprecipitation (IP) in myoblasts (Figures S6P and S6Q) revealed that circ-ZNF609 is highly methylated, suggesting a possible regulatory role of this modification in circ-ZNF609 translational ”