FTO-Dependent N 6 -Methyladenosine Regulates Cardiac Function During Remodeling and Repair DOI Open Access
Prabhu Mathiyalagan, Mateusz Adamiak, Joshua Mayourian

et al.

Circulation, Journal Year: 2018, Volume and Issue: 139(4), P. 518 - 532

Published: July 11, 2018

Background: Despite its functional importance in various fundamental bioprocesses, studies of N 6 -methyladenosine (m6A) the heart are lacking. Here, we show that FTO (fat mass and obesity-associated protein), an m6A demethylase, plays a critical role cardiac contractile function during homeostasis, remodeling, regeneration. Methods: We used clinical human samples, preclinical pig mouse models, primary cardiomyocyte cell cultures to study cardiomyocytes. modulated expression by using adeno-associated virus serotype 9 (in vivo), adenovirus (both vivo vitro), small interfering RNAs vitro) regulating m6A, calcium dynamics contractility, postischemia. performed methylated RNA immunoprecipitation sequencing map transcriptome-wide quantitative polymerase chain reaction assays validate individual transcripts, healthy failing hearts, myocytes. Results: discovered has decreased mammalian hearts hypoxic cardiomyocytes, thereby increasing decreasing function. Improving attenuated ischemia-induced increase decrease This is demethylation activity FTO, which selectively demethylates thus preventing their degradation improving protein under ischemia. In addition, demonstrate overexpression models myocardial infarction fibrosis enhanced angiogenesis. Conclusions: Collectively, our demonstrates FTO-dependent methylome contraction failure provides novel mechanistic insight into therapeutic mechanisms FTO.

Language: Английский

Dynamic RNA Modifications in Gene Expression Regulation DOI Creative Commons

Ian A. Roundtree,

Molly Evans, Tao Pan

et al.

Cell, Journal Year: 2017, Volume and Issue: 169(7), P. 1187 - 1200

Published: June 1, 2017

Language: Английский

Citations

2809
Post-transcriptional gene regulation by mRNA modifications DOI Open Access
Boxuan Simen Zhao,

Ian A. Roundtree,

Chuan He

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2016, Volume and Issue: 18(1), P. 31 - 42

Published: Nov. 3, 2016

Language: Английский

Citations

1966
Reading, writing and erasing mRNA methylation DOI
Sara Zaccara, Ryan J. Ries, Samie R. Jaffrey

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2019, Volume and Issue: 20(10), P. 608 - 624

Published: Sept. 13, 2019

Language: Английский

Citations

1933
Where, When, and How: Context-Dependent Functions of RNA Methylation Writers, Readers, and Erasers DOI Creative Commons
Hailing Shi, Jiangbo Wei, Chuan He

et al.

Molecular Cell, Journal Year: 2019, Volume and Issue: 74(4), P. 640 - 650

Published: May 1, 2019

Language: Английский

Citations

1491
FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N 6 -Methyladenosine RNA Demethylase DOI Creative Commons
Zejuan Li, Hengyou Weng, Rui Su

et al.

Cancer Cell, Journal Year: 2016, Volume and Issue: 31(1), P. 127 - 141

Published: Dec. 23, 2016

Language: Английский

Citations

1296
m 6 A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program DOI Creative Commons
Sicong Zhang, Boxuan Simen Zhao, Aidong Zhou

et al.

Cancer Cell, Journal Year: 2017, Volume and Issue: 31(4), P. 591 - 606.e6

Published: March 23, 2017

Language: Английский

Citations

1283
RNA N6‐methyladenosine methyltransferase‐like 3 promotes liver cancer progression through YTHDF2‐dependent posttranscriptional silencing of SOCS2 DOI Creative Commons

Mengnuo Chen,

Lai Wei, Cheuk‐Ting Law

et al.

Hepatology, Journal Year: 2017, Volume and Issue: 67(6), P. 2254 - 2270

Published: Nov. 24, 2017

Epigenetic alterations have contributed greatly to human carcinogenesis. Conventional epigenetic studies predominantly focused on DNA methylation, histone modifications, and chromatin remodeling. Recently, diverse reversible chemical modifications of RNAs emerged as a new layer regulation. N6‐methyladenosine (m6A) is the most abundant modification eukaryotic messenger RNA (mRNA) important for regulation mRNA stability, splicing, translation. Using transcriptome sequencing, we discovered that methyltransferase‐like 3 (METTL3), major N6‐adenosine methyltransferase, was significantly up‐regulated in hepatocellular carcinoma (HCC) multiple solid tumors. Clinically, overexpression METTL3 associated with poor prognosis patients HCC. Functionally, proved knockdown drastically reduced HCC cell proliferation, migration, colony formation vitro . Knockout remarkably suppressed tumorigenicity lung metastasis vivo On other hand, using CRISPR/dCas9‐VP64 activation system, demonstrated promoted growth both Through m6A methylated immuno‐precipitation quantitative reverse‐transcription polymerase chain reaction, identified suppressor cytokine signaling 2 (SOCS2) target METTL3‐mediated modification. Knockdown substantially abolished SOCS2 augmented expression. We also showed m6A‐mediated degradation relied reader protein YTHDF2‐dependent pathway. Conclusion : frequently contributes progression. represses expression through an m6A‐YTHDF2‐dependent mechanism. Our findings suggest mechanism alteration liver (H epatology 2018;67:2254‐2270).

Language: Английский

Citations

1122
Functions of N6-methyladenosine and its role in cancer DOI Creative Commons

Liuer He,

Huiyu Li,

Anqi Wu

et al.

Molecular Cancer, Journal Year: 2019, Volume and Issue: 18(1)

Published: Dec. 1, 2019

N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A installed by methyltransferases, removed demethylases recognized reader proteins, regulate RNA metabolism including translation, splicing, export, degradation microRNA processing. Alteration levels participates cancer pathogenesis development via expression tumor-related genes like BRD4, MYC, SOCS2 EGFR. In this review, we elaborate recent advances research enzymes. We also highlight underlying mechanism progression. Finally, review corresponding potential targets therapy.

Language: Английский

Citations

1105
m 6 A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells DOI Creative Commons
Qi Cui, Hailing Shi, Peng Ye

et al.

Cell Reports, Journal Year: 2017, Volume and Issue: 18(11), P. 2622 - 2634

Published: March 1, 2017

Highlights•The self-renewal of GSCs is regulated by m6A RNA methylation•Reduced methylation promotes the tumorigenesis GSCs•An FTO inhibitor suppresses progression GSC-initiated tumor•m6A-seq reveals transcriptome-wide mRNA modification and regulation in GSCsSummaryRNA modifications play critical roles important biological processes. However, functions N6-methyladenosine (m6A) cancer biology stem cells remain largely unknown. Here, we show that for glioblastoma cell (GSC) tumorigenesis. Knockdown METTL3 or METTL14, key components methyltransferase complex, dramatically human GSC growth, self-renewal, In contrast, overexpression inhibition demethylase growth self-renewal. Moreover, tumor prolongs lifespan GSC-grafted mice substantially. sequencing knockdown METTL14 induced changes enrichment altered expression genes (e.g., ADAM19) with GSCs. summary, this study identifies machinery as promising therapeutic targets glioblastoma.Graphical abstract

Language: Английский

Citations

1102
RNA modifications modulate gene expression during development DOI Open Access
Michaela Frye, Bryan T. Harada, Mikaela Behm

et al.

Science, Journal Year: 2018, Volume and Issue: 361(6409), P. 1346 - 1349

Published: Sept. 28, 2018

RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programs. They affect diverse eukaryotic biological processes, and the correct deposition many these is required for normal development. Messenger (mRNA) regulate various aspects mRNA metabolism. For example,

Language: Английский

Citations

987