METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer’s disease through aberrant cell cycle events DOI Creative Commons
Fanpeng Zhao, Ying Xu,

Shichao Gao

et al.

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Sept. 30, 2021

N6-methyladenosine (m6A) modification of RNA influences fundamental aspects metabolism and m6A dysregulation is implicated in various human diseases. In this study, we explored the potential role pathogenesis Alzheimer disease (AD).We investigated expression regulators brain tissues AD patients determined impact underlying mechanism manipulated levels on AD-related deficits both vitro vivo.We found decreased neuronal along with significantly reduced methyltransferase like 3 (METTL3) brains. Interestingly, hippocampus caused by METTL3 knockdown led to significant memory deficits, accompanied extensive synaptic loss death multiple cellular alterations including oxidative stress aberrant cell cycle events vivo. Inhibition or alleviated shMettl3-induced apoptotic activation damage primary neurons. Restored inhibiting its demethylation rescued abnormal events, induced knockdown. Soluble Aβ oligomers exacerbated while overexpression Aβ-induced PSD95 vitro. Importantly, cognitive impairment vivo.Collectively, these data suggested that reduction-mediated likely contributes neurodegeneration which may be a therapeutic target for AD.

Language: Английский

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

1474
The role of m6A modification in the biological functions and diseases DOI Creative Commons
Xiulin Jiang, Baiyang Liu, Zhi Nie

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Feb. 21, 2021

Abstract N 6 -methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher cells. m6A modified by methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, KIAA1429, and, removed demethylases, erasers, including FTO ALKBH5. It recognized m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 HNRNPA2B1, also known “readers”. Recent studies have shown that RNA plays essential role both physiological pathological conditions, initiation progression of different types human cancers. In this review, we discuss how methylation influences progressions hematopoietic, central nervous reproductive systems. We will mainly focus on recent progress identifying biological functions underlying molecular mechanisms methylation, its regulators downstream target genes, during cancer above propose process offer potential targets for therapy future.

Language: Английский

Citations

1400
Intrinsic mechanisms of neuronal axon regeneration DOI
Marcus Mahar, Valeria Cavalli

Nature reviews. Neuroscience, Journal Year: 2018, Volume and Issue: 19(6), P. 323 - 337

Published: April 17, 2018

Language: Английский

Citations

510
m 6 A RNA methylation: from mechanisms to therapeutic potential DOI Open Access
P. Cody He, Chuan He

The EMBO Journal, Journal Year: 2021, Volume and Issue: 40(3)

Published: Jan. 20, 2021

Language: Английский

Citations

504
m6A facilitates hippocampus-dependent learning and memory through YTHDF1 DOI
Hailing Shi, Xuliang Zhang,

Yi-Lan Weng

et al.

Nature, Journal Year: 2018, Volume and Issue: 563(7730), P. 249 - 253

Published: Oct. 30, 2018

Language: Английский

Citations

440
Accurate detection of m6A RNA modifications in native RNA sequences DOI Creative Commons
Huanle Liu, Oguzhan Begik, Morghan C. Lucas

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Sept. 9, 2019

Abstract The epitranscriptomics field has undergone an enormous expansion in the last few years; however, a major limitation is lack of generic methods to map RNA modifications transcriptome-wide. Here, we show that using direct sequencing, N 6 -methyladenosine (m A) can be detected with high accuracy, form systematic errors and decreased base-calling qualities. Specifically, find our algorithm, trained m A-modified unmodified synthetic sequences, predict A ~90% accuracy. We then extend findings yeast data sets, finding method identify vivo accuracy 87%. Moreover, further validate by showing these ‘errors’ are typically not observed ime4 -knockout strains, which modifications. Our results open avenues investigate biological roles their native context.

Language: Английский

Citations

437
DART-seq: an antibody-free method for global m6A detection DOI
Kate D. Meyer

Nature Methods, Journal Year: 2019, Volume and Issue: 16(12), P. 1275 - 1280

Published: Sept. 23, 2019

Language: Английский

Citations

379
The m6A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network DOI Open Access
Maosheng Cheng, Sheng Lu, Qian Gao

et al.

Oncogene, Journal Year: 2019, Volume and Issue: 38(19), P. 3667 - 3680

Published: Jan. 18, 2019

Language: Английский

Citations

330
Cap-specific terminal N 6 -methylation of RNA by an RNA polymerase II–associated methyltransferase DOI Open Access
Shinichiro Akichika, Seiichi Hirano, Yuichi Shichino

et al.

Science, Journal Year: 2018, Volume and Issue: 363(6423)

Published: Nov. 23, 2018

A cap-specific m 6 writer N ,2′- O -dimethyladenosine (m Am) is present at the transcription start nucleotide of capped mRNAs in vertebrates. Akichika et al. quantified abundance this modification transcriptome and identified protein, adenosine methyltransferase (CAPAM), needed for modification. CAPAM contains a unique structure that recognizes -methyladenosine A) as substrate. The protein interacts with RNA polymerase II, suggesting occurs cotranscriptionally. Am promotes translation eIF4E-independent fashion. Science , issue p. eaav0080

Language: Английский

Citations

321
A novel m6A reader Prrc2a controls oligodendroglial specification and myelination DOI Creative Commons
Rong Wu, Ang Li, Baofa Sun

et al.

Cell Research, Journal Year: 2018, Volume and Issue: 29(1), P. 23 - 41

Published: Dec. 4, 2018

While N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, is linked to cell differentiation and tissue development, biological significance of m6A mammalian glial development remains unknown. Here, we identify a novel reader, Prrc2a (Proline rich coiled-coil 2 A), which controls oligodendrocyte specification myelination. Nestin-Cre-mediated knockout induces significant hypomyelination, decreased lifespan, as well locomotive cognitive defects mouse model. Further analyses reveal that involved progenitor cells (OPCs) proliferation fate determination. Accordingly, oligodendroglial-lineage specific deletion causes similar phenotype deletion. Combining transcriptome-wide RNA-seq, m6A-RIP-seq RIP-seq analysis, find Olig2 critical downstream target gene development. Furthermore, stabilizes mRNA through binding consensus GGACU motif CDS (coding sequence) an m6A-dependent manner. Interestingly, also demethylase, Fto, erases promotes its degradation. Together, our results indicate plays important role functioning reader. These findings suggest new avenue for therapeutic strategies hypomyelination-related neurological diseases.

Language: Английский

Citations

309