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FTO Regulates Activation of Rho GTPases Signaling as N6-methyladenosine RNA Demethylase and an Rhotekin Partner Protein

ABSTRACT: Reversible RNA modification of N6-methyladenosine (m6A) plays a critical role in post-transcriptional gene regulation1-13. Although the fat mass and obesity-associated protein (FTO) has been previously shown to function as an m6A demethylase in nuclear RNA1,14, its exact function in disease pathogenesis remains a mystery. Here, we demonstrate that FTO suppresses the activation of Rho GTPase signaling via both its demethylation activity and specific interaction with Rho effector, Rhotekin (RTKN)15. The knockdown of FTO activates RhoA and RhoC, induces stress fibres, and accelerates cell migration. Endogenous RTKN is highly expressed in certain cancer and cancer-derived cell lines16,17 with overexpression of RTKN leading to moderate activation of Rho18. We further found that overexpression of RTKN blocks nuclear import of FTO and traps FTO in the cytoplasm to mediate m6A demethylation of cytosolic mRNA, thereby changing gene expression by preventing m6A-dependent mRNA decay and translation. Our results illustrate how FTO represses Rho activation through m6A demethylation and direct interaction with RTKN, and shed new light on FTO-dependent post-transcriptional gene regulation in RTKN overexpressed cancers, which may provide a new direction for developing anti-cancer therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83540 | GEO | 2018/12/31

REPOSITORIES: GEO

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Quantitative Proteomics of Mouse Liver (FTO-KO,WT) in response to DEN injection

Project description:Single nucleotide polymorphisms in the FTO gene encoding a m6A demthylase are associated with obesity and cancer development. However, the functional role of FTO in the developemnt of progression of hepatocellular carcinoma (HCC) as a proteotypic obesity-associated cancer remains unclear. Here, we have generated mice with hepatic FTO deficiency (FTOL-KO) and subjected them to DEN induced HCC-development. FTOL-KO mice exhibit increased HCC burden. While control mice exhibit a dynamic regulation of FTO upon induction of liver damage, this response is abrogated in mice lacking FTO. Proteomic analyses revealed that liver damage-induced increases in FTO expression promotes m6A-demethylation of CUL4A reducing its protein expression. Functionally, knockdown of CUL4A restores the increased hepatocyte proliferation observed upon loss of FTO. Collectively, our study reveals a protective role for FTO-dependent dynamic m6A mRNA demethylation of CUL4A in the initiation of HCC development.

2020-11-03 | PXD018223 | Pride

The Obesity-associated Fto gene regulates activity of the dopaminergic midbrain circuitry [FTO KO]

Project description:Here we use MeRIP-Seq to analyze global adenosine methylation (m6A) in mRNAs in the midbrain and striatum of Fto-deficient mice. We find that Fto deficiency leads to increased methylation within a subset of mRNAs important for neuronal signaling, including many within the dopaminergic signaling pathway. Collectively, our results show that Fto regulates demethylation of specific mRNAs in vivo, and this activity relates to control of dopaminergic transmission. Profiling of m6A in midbrain and striatum from FTO knockout mice

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Project description:The fat mass and obesity-associated (FTO) protein is a well-characterized demethylase that removes N6-methyladenosine (m6A) from animal mRNAs. However, it is unclear yet how the demethylation operates in living cells. In this study, we applied genome-wide approaches to study how FTO finds its demethylation targets in human cells. We overexpressed FTO in human HeLa cells, demonstrating that FTO effectively removes m6A from the RRACH motif enriched in the 3’UTR regions and leaves m6A at other motifs unaffected. RRACH elements are clearly enriched at FTO binding sites; however, m6A has a lower tendency to be removed from the FTO-bound RRACH. Taken together with the experimental validaton results, we propose a model in which FTO effectivly recognizes m6A-containing RRACH motifs in RNAs, leading to a faster demethylation and dissociation kinetic than the association, and consequently undectable FTO-mRNA association. However, when FTO binds to the non-m6A RRACH motif, the binding has a lower dissociation kinetics, yielding the detectable FTO binding signals which would enable FTO to have roles in regulating other mRNA processing events.

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