Sequencing of mRNA with N6-methyladenosine (m6A) modification in AML cells upon DMSO or FTO inhibitor treatment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE103496 | GEO | 2019/04/29
REPOSITORIES: GEO
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Project description:To determine the potential targets of FTO and identify treatment significance of FTO inhibition in AML, we conducted transcriptome wide RNA seq with NB4 cells upon DMSO and FTO inhibitors (FB23 and FB23-2) treatment.
2019-04-29 | GSE103495 | GEO
Project description:FTO, an N6-methyladenosine demethylase, has emerged as a promising target for the treatment of specific acute myeloid leukemia (AML) subtypes. Here, we investigate the antiproliferative effects of the FTO inhibitor FB23-2 in leukemia. We demonstrate that FB23-2 potently inhibits proliferation across both AML and CML cell lines, irrespective of their responsiveness to FTO depletion. Interestingly, FB23-2 induces cell cycle arrest without a concurrent increase in m6A levels, suggesting an alternative mechanism of action.
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Project description:To identify potential mRNA targets of FTO whose m6A levels are influenced in acute myeloid leukemia (AML) cells, we conducted m6A-seq for mRNA isolated from MA9.3ITD cells with and without knockdown of FTO
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Project description:N6-methyladenosine (m6A) modification of messenger RNAs (mRNAs) is a pivotal mechanism controlling mRNA fate in cells. RNA m6A modification is regulated by the functional balance between methyltransferases and demethylases. Here we demonstrated that FTO-IT1 enhancer RNA (eRNA), a long non-coding RNA (lncRNA) transcribed from the last intron of FTO gene is significantly upregulated in CRPC and aggressive tumors compared to primary tumors. FTO-IT1 knockout by CRISPR/Cas9 almost completely blocks growth and G1-S cell cycle transition of both androgen-sensitive and castration-resistant prostate cancer cells. Meanwhile, the mRNA m6A was dramatically increased in FTO-IT knockout PCa cells and we identified FTO-IT1 as a binding partner of FTO. From m6A-seq, we unexpectedly found hypermethylated m6A associated with upregulated levels of the mRNAs for p53 signaling pathway genes in 22Rv1 prostate cancer cells. Mechanistic study showed that FTO-IT1 recruits FTO to the P53 target mRNA to promote their m6A demethylation, which leads to their degradation.
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Project description:Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays a critical oncogenic role in various cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in clinical patients of HCC and presents as a poor prognostic factor. Genetic depletion of FTO dramatically attenuated HCC progression in vivo. Pharmacological inhibition of FTO by FB23/FB23-2 remarkably suppressed the proliferation and migration of HCC cell lines in vitro, as well as inhibiting the HCC tumorigenicity in xeno-transplanted mice. Mechanistically, FB23-2 suppressed the expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) and human tubulin beta class Iva (TUBB4A) by increasing the m6A level in these mRNA transcripts. The decreased ERBB3 resulted in inhibited Akt-mTOR signaling that subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 abolished the organization of the tubulin cytoskeleton, while enforced expression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrated that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells, and highlights the broad potential of FTO inhibitors for targeting HCC.
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Project description:To identify potential mRNA targets of FTO whose m6A levels are affected by FTO in acute myeloid leukemia (AML) cells, we conducted m6A-seq for messenger RNAs isolated from AML cells with and without forced expression of FTO.
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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.
2020-03-22 | GSE101954 | GEO
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.
2020-03-22 | GSE101953 | GEO
Project description:Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays a critical oncogenic role in various cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in clinical patients of HCC and presents as a poor prognostic factor. Genetic depletion of FTO dramatically attenuated HCC progression in vivo. Pharmacological inhibition of FTO by FB23/FB23-2 remarkably suppressed the proliferation and migration of HCC cell lines in vitro, as well as inhibiting the HCC tumorigenicity in xeno-transplanted mice. Mechanistically, FB23-2 suppressed the expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) and human tubulin beta class Iva (TUBB4A) by increasing the m6A level in these mRNA transcripts. The decreased ERBB3 resulted in inhibited Akt-mTOR signaling that subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 abolished the organization of the tubulin cytoskeleton, while enforced expression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrated that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells, and highlights the broad potential of FTO inhibitors for targeting HCC.
2025-01-03 | GSE268326 | GEO
Project description:Fat mass and obesity-associated gene (FTO) is a member of the Fe (II) and oxoglutarate-dependent AlkB oxygenase family, and has been linked to obesity and intellectual disability. However, the role of FTO in neurodevelopment and neurogenesis remains largely unknown. Here, we show that FTO is expressed in adult neural stem cells (aNSCs) and neurons, and displays dynamic expression during postnatal neurodevelopment. The loss of FTO leads to the decreased brain size and body weight. We found that FTO deficiency could reduce the proliferation and neuronal differentiation of aNSCs in vivo, which leads to the impaired learning and memory. Given the role of FTO as a demethylase of N6-methyladenosine (m6A), we further performed the genome-wide m6A profiling and observed the dynamic m6A modification during postnatal neurodevelopment. The loss of FTO could lead to the altered m6A modifications on the mRNAs of several key components of BDNF pathway. These results together suggest that FTO play important roles in neurogenesis and learning and memory.
2017-04-20 | GSE94098 | GEO