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

Ythdf2-mediated m6A mRNA clearance modulates neural development in mice DOI Creative Commons
Miaomiao Li, Xu Zhao, Wei Wang

et al.

Genome biology, Journal Year: 2018, Volume and Issue: 19(1)

Published: May 31, 2018

N 6 -methyladenosine (m6A) modification in mRNAs was recently shown to be dynamically regulated, indicating a pivotal role multiple developmental processes. Most recently, it that the Mettl3-Mettl14 writer complex of this mark is required for temporal control cortical neurogenesis. The m6A reader protein Ythdf2 promotes mRNA degradation by recognizing and recruiting decay machinery.We show conditional depletion mice causes lethality at late embryonic stages, with embryos characterized compromised neural development. We demonstrate stem/progenitor cell (NSPC) self-renewal spatiotemporal generation neurons other types are severely impacted loss neocortex. Combining vivo vitro assays, we proliferation differentiation capabilities NSPCs decrease significantly -/- embryos. unable produce normally functioning neurites, leading failure recovery upon reactive oxygen species stimulation. Consistently, expression genes enriched development pathways disturbed. Detailed analysis m6A-methylomes identifies JAK-STAT cascade inhibitory contribute neuroprotection neurite outgrowths increased enrichment. In agreement function Ythdf2, delayed neuron differentiation-related m6A-containing seen NSPCs.We modulates promoting m6A-dependent development-related targets.

Language: Английский

Citations

300
METTL3-mediated m6A modification is required for cerebellar development DOI Creative Commons
Chenxin Wang, Guanshen Cui, Xiuying Liu

et al.

PLoS Biology, Journal Year: 2018, Volume and Issue: 16(6), P. e2004880 - e2004880

Published: June 7, 2018

N6-methyladenosine (m6A) RNA methylation is the most abundant modification on mRNAs and plays important roles in various biological processes. The formation of m6A catalyzed by a methyltransferase complex including methyltransferase-like 3 (METTL3) as key factor. However, vivo functions METTL3 mammalian development remain unclear. Here, we show that specific inactivation Mettl3 mouse nervous system causes severe developmental defects brain. conditional knockout (cKO) mice manifest cerebellar hypoplasia caused drastically enhanced apoptosis newborn granule cells (CGCs) external granular layer (EGL). depletion–induced loss extended half-lives aberrant splicing events, consequently leading to dysregulation transcriptome-wide gene expression premature CGC death. Our findings reveal critical role METTL3-mediated regulating cerebellum.

Language: Английский

Citations

254
The m6A epitranscriptome: transcriptome plasticity in brain development and function DOI
Ido Livneh, Sharon Moshitch-Moshkovitz, Ninette Amariglio

et al.

Nature reviews. Neuroscience, Journal Year: 2019, Volume and Issue: 21(1), P. 36 - 51

Published: Dec. 5, 2019

Language: Английский

Citations

254
The role of N6-methyladenosine (m6A) modification in the regulation of circRNAs DOI Creative Commons
Lele Zhang,

Chaofeng Hou,

Chen Chen

et al.

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: June 10, 2020

N6-methyladenosine (m6A), the most abundant modification in eukaryotic cells, regulates RNA transcription, processing, splicing, degradation, and translation. Circular (circRNA) is a class of covalently closed molecules characterized by universality, diversity, stability conservatism evolution. Accumulating evidence shows that both m6A circRNAs participate pathogenesis multiple diseases, such as cancers, neurological autoimmune infertility. Recently, has been identified for its enrichment vital biological functions regulating circRNAs. In this review, we summarize role regulation function Moreover, discuss potential applications possible future directions field.

Language: Английский

Citations

236
Abnormality of m6A mRNA Methylation Is Involved in Alzheimer’s Disease DOI Creative Commons

Min Han,

Zhen Liu, Yingying Xu

et al.

Frontiers in Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: Feb. 28, 2020

Alzheimer's disease (AD), the most common form of dementia, is highly prevalent in older adults. The main clinical feature progressive decline memory function, which eventually leads to cognitive function. At present, pathogenesis AD unclear. In process, synaptic changes are key. Recent studies have shown that dysregulation RNA methylation related many biological processes, including neurodevelopment and neurodegenerative diseases. N6-methyladenosine (m6A) abundant modification eukaryotic RNA. this study, m6A was quantified APP/PS1 transgenic mice, an mouse model, C57BL/6 control data showed elevated cortex hippocampus mice. Next, alterations mice were investigated using high-throughput sequencing. Genome-wide maps mRNA degrees higher genes lower others Interestingly, expression methyltransferase METTL3 demethylase FTO decreased analyzed by gene ontology (GO) Kyoto Encyclopedia Genes Genomes (KEGG) pathway analyses, pathways might be or neuron development growth constructed. predicted potential roles differentially expressed AD. Collectively, our findings demonstrate promotes

Language: Английский

Citations

234
RNA m6A methylation participates in regulation of postnatal development of the mouse cerebellum DOI Creative Commons
Chunhui Ma, Mengqi Chang,

Hongyi Lv

et al.

Genome biology, Journal Year: 2018, Volume and Issue: 19(1)

Published: May 31, 2018

N6-methyladenosine (m6A) is an important epitranscriptomic mark with high abundance in the brain. Recently, it has been found to be involved regulation of memory formation and mammalian cortical neurogenesis. However, while now established that m6A methylation occurs a spatially restricted manner, its functions specific brain regions still await elucidation. We identify widespread dynamic RNA developing mouse cerebellum further uncover distinct features continuous temporal-specific across four postnatal developmental processes. Temporal-specific peaks from P7 P60 exhibit remarkable changes their distribution patterns along mRNA transcripts. also show spatiotemporal-specific expression writers METTL3, METTL14, WTAP erasers ALKBH5 FTO cerebellum. Ectopic METTL3 mediated by lentivirus infection leads disorganized structure both Purkinje glial cells. In addition, under hypobaric hypoxia exposure, Alkbh5-deletion causes abnormal cell proliferation differentiation through disturbing balance different fate determination genes. Notably, nuclear export hypermethylated RNAs enhanced Alkbh5-deficient mice exposed hypoxia. Together, our findings provide strong evidence controlled precise spatiotemporal manner participates development

Language: Английский

Citations

220
N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer’s disease DOI Creative Commons
Andrew M. Shafik, Feiran Zhang, Zhenxing Guo

et al.

Genome biology, Journal Year: 2021, Volume and Issue: 22(1)

Published: Jan. 5, 2021

N6-methyladenosine (m

Citations

196
METTL3-mediated N6-methyladenosine mRNA modification enhances long-term memory consolidation DOI Creative Commons
Zeyu Zhang, Meng Wang,

Dongfang Xie

et al.

Cell Research, Journal Year: 2018, Volume and Issue: 28(11), P. 1050 - 1061

Published: Oct. 8, 2018

The formation of long-term memory is critical for learning ability and social behaviors humans animals, yet its underlying mechanisms are largely unknown. We found that the efficacy hippocampus-dependent consolidation regulated by METTL3, an RNA N6-methyladenosine (m6A) methyltransferase, through promoting translation neuronal early-response genes. Such effect exquisitely dependent on m6A methyltransferase function METTL3. Depleting METTL3 in mouse hippocampus reduces ability, unimpaired outcomes can be achieved if adequate training was given or restored. abundance wild-type positively correlated with efficacy, overexpression significantly enhances consolidation. These findings uncover a direct role modification regulating formation, also indicate difference among individuals could compensated repeated learning.

Language: Английский

Citations

180
Chemical Modifications in the Life of an mRNA Transcript DOI Open Access
Sigrid Nachtergaele, Chuan He

Annual Review of Genetics, Journal Year: 2018, Volume and Issue: 52(1), P. 349 - 372

Published: Sept. 19, 2018

Investigations over the past eight years of chemical modifications on messenger RNA (mRNA) have revealed a new level posttranscriptional gene regulation in eukaryotes. Rapid progress our understanding these modifications, particularly, N 6 -methyladenosine (m A), has their roles throughout life cycle an mRNA transcript. m A methylation provides rapid mechanism for coordinated transcriptome processing and turnover that is important embryonic development cell differentiation. In response to cellular signals, can also regulate translation specific pools transcripts. These mechanisms be hijacked human diseases, including numerous cancers viral infection. Beyond A, many other been mapped transcriptome, but much less known about biological functions. As methods continue developed, we will able study both more broadly greater depth, which likely reveal wealth biology.

Language: Английский

Citations

177
The m6A reader YTHDF1 regulates axon guidance through translational control of Robo3.1 expression DOI Creative Commons

Mengru Zhuang,

Xinbei Li, Junda Zhu

et al.

Nucleic Acids Research, Journal Year: 2019, Volume and Issue: 47(9), P. 4765 - 4777

Published: Feb. 27, 2019

N 6-Methyladenosine (m6A) is a dynamic mRNA modification which regulates protein expression in various posttranscriptional levels. Functional studies of m6A nervous system have focused on its writers and erasers so far, whether how readers mediate functions through recognizing binding their target remains poorly understood. Here, we find that the axon guidance receptor Robo3.1 plays important roles midline crossing spinal commissural axons regulated precisely at translational level. The reader YTHDF1 binds to positively translation m6A-modified mRNA. Either mutation sites or knockdown knockout leads dramatic reduction without affecting Specific ablation Ythdf1 neurons results pre-crossing defects. Our findings identify mechanism YTHDF1-mediated controls cord.

Language: Английский

Citations

168