Comprehensive analysis of N6-methyladenosine (m6A) modification during the degeneration of lumbar intervertebral disc in mice

Zhu, Bin; Chen, Haoxiang; Li, Shan; Tan, Jing‐Hua; Xie, Yuan; Zou, Ming-Xiang; Wang, Cheng; Xue, Jing; Li, Xuelin; Cao, Yong; Yan, Yongping

doi:10.1016/j.jot.2021.10.008

Cited by 13 publications

(13 citation statements)

References 55 publications

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“…Our data indicated that m6A regulation was complex. Both hypomethylated and hypermethylated m6A could induce or reduce mRNA expression, which was consistent with previous studies 34,35 . The differentially expressed genes with altered m6A methylation included small proline-rich repeat protein 1A (sprr1a), c-type lectin domain family 4 member D (clec4d) and apelin receptor (aplnr).…”

Section: Discussionsupporting

confidence: 93%

“…Both hypomethylated and hypermethylated m6A could induce or reduce mRNA expression, which was consistent with previous studies. 36,37 The differentially expressed genes with altered m6A methylation included small proline-rich repeat protein 1A (sprr1a), c-type lectin domain family 4 member D (clec4d) and apelin receptor (aplnr). Sprr1a is highly expressed in injured neurons and thought to be a regeneration-associated gene (REG) that promotes spontaneous axon growth.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive analysis of m6A methylation modification in chronic spinal cord injury in mice

Liu

Zhao

Qin

et al. 2022

Journal Orthopaedic Research

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Chronic spinal cord injury (CSCI) is a catastrophic disease of the central nervous system (CNS), resulting in partial or complete loss of neurological function. N6-methyladenosine (m6A) is the most common form of reversible posttranslational modi cation at the RNA level. However, the role of m6A modi cation in CSCI remains unknown. In this study, we established a CSCI model using a water-absorbable polyurethane polymer, with behavioral assessment, electrophysiological analysis, and histochemical staining for validation. Methylated RNA immunoprecipitation sequencing (meRIP-seq) and mRNA sequencing (mRNA-seq) were jointly explored to compare the differences in CSCI spinal tissue and normal spinal tissue. Furthermore, qRT-PCR, western blotting, and immuno uorescence staining were used to analyze m6A modi cation-related proteins. We found that water-absorbable polyurethane polymer well simulated chronic spinal cord compression. BMS scores and electrophysiological analysis showed continuous neurological function decline after chronic compression of the spinal cord. meRIP-seq identi ed 642 differentially modi ed m6A genes, among which 263 genes were downregulated and 379 genes were upregulated. mRNA-seq showed that 1544 genes were upregulated and 290 genes were downregulated after CSCI. Gene Ontology (GO) terms and enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were also identi ed. qRT-PCR, western blotting, and immuno uorescence staining showed that Mettl14 was signi cantly upregulated after CSCI. Our study revealed a comprehensive pro le of m6A modi cations in CSCI and may provide a valuable tool for further research on CSCI. study showed that mettl14 was signi cantly overexpressed after CSCI and mainly expressed in neurons, which was further validated by qRT-PCR, western blotting, and immuno uorescence.Our study is not without limitations. First, we obtained whole spinal tissue for meRIP-seq and mRNA-seq. Although the total m6A modi cations were assessed, it was di cult to distinguish m6A methylation changes in speci c cell types. In further in-depth research, extracting speci c cells for veri cation of m6A modi cation and exploring its function would be meaningful. Second, we performed preliminary analyses of differentially expressed genes and enriched GO and KEGG pathways, but their roles in CSCI require further validation through extensive experiments.Collectively, our study analyzed m6A methylation modi cations in spinal cord tissue after CSCI. The results indicated that m6A plays an important role in the process of CSCI. Our research may provide new insights for further study of the CSCI pathological process and potential treatment options. DeclarationsAuthor contributions JH, YC and HL designed the study. CL and JZ carried out most of the experiments and data analysis. YJ, TQ, CD and TW assisted in experiments and data analysis. CL drafted the manuscript, and JH and YC revised the manuscript.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of m6A methylation modification in chronic spinal cord injury in mice

Liu

Zhao

Qin

et al. 2022

Journal Orthopaedic Research

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“…NPC is exposed to various stress environments, and stress is an upstream regulatory signal of m6A in NPC. Zhu, Chen, et al (2021). established a standing mouse model to induce IDD by enhancing the mechanical compression of IVD.…”

Section: Npc Autophagy Under Stress Is Possibly Mediated By M6a Methy...mentioning

confidence: 99%

M6A methylation‐regulated autophagy may be a new therapeutic target for intervertebral disc degeneration

Tao,

Yu,

et al. 2024

Cell Biology International

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Degeneration of intervertebral discs is considered one of the most important causes of low back pain and disability. The intervertebral disc (IVD) is characterized by its susceptibility to various stressors that accelerate the senescence and apoptosis of nucleus pulposus cells, resulting in the loss of these cells and dysfunction of the intervertebral disc. Therefore, how to reduce the loss of nucleus pulposus cells under stress environment is the main problem in treating intervertebral disc degeneration. Autophagy is a kind of programmed cell death, which can provide energy by recycling substances in cells. It is considered to be an effective method to reduce the senescence and apoptosis of nucleus pulposus cells under stress. However, further research is needed on the mechanisms by which autophagy of nucleus pulposus cells is regulated under stress environments. M6A methylation, as the most extensive RNA modification in eukaryotic cells, participates in various cellular biological functions and is believed to be related to the regulation of autophagy under stress environments, may play a significant role in nucleus pulposus responding to stress. This article first summarizes the effects of various stressors on the death and autophagy of nucleus pulposus cells. Then, it summarizes the regulatory mechanism of m6A methylation on autophagy‐related genes under stress and the role of these autophagy genes in nucleus pulposus cells. Finally, it proposes that the methylation modification of autophagy‐related genes regulated by m6A may become a new treatment approach for intervertebral disc degeneration, providing new insights and ideas for the clinical treatment of intervertebral disc degeneration.

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“…These regions overlapped spatially with the enhancer-binding region of the serine- and arginine-rich splicing factor (SRSF), which modulated mRNA splicing ( Zhao et al, 2014 ). It has been suggested that depletion of FTO enhanced the m6A level and promoted the affinity of SRSF2 binding with RNA, thereby increasing the number of target exons and inducing RNA maturation ( Zhu et al, 2021 ). Furthermore, the m6A reader YTHDC1 could recruit the splicing factor SRSF3 to promote exon inclusion but antagonize SRSF10 mRNA binding, which facilitated exon skipping ( Xiao et al, 2016 ).…”

Section: Crosstalk Between N6-methyladenosine Modification and Rnas I...mentioning

confidence: 99%

Crosstalk among N6-methyladenosine modification and RNAs in central nervous system injuries

Tian

Mao

Zhang

2022

Front. Cell. Neurosci.

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Central nervous system (CNS) injuries, including traumatic brain injury (TBI), intracerebral hemorrhage (ICH) and ischemic stroke, are the most common cause of death and disability around the world. As the most common modification on ribonucleic acids (RNAs), N6-methyladenosine (m6A) modification has recently attracted great attentions due to its functions in determining the fate of RNAs through changes in splicing, translation, degradation and stability. A large number of studies have suggested that m6A modification played an important role in brain development and involved in many neurological disorders, particularly in CNS injuries. It has been proposed that m6A modification could improve neurological impairment, inhibit apoptosis, suppress inflammation, reduce pyroptosis and attenuate ferroptosis in CNS injuries via different molecules including phosphatase and tensin homolog (PTEN), NLR family pyrin domain containing 3 (NLRP3), B-cell lymphoma 2 (Bcl-2), glutathione peroxidase 4 (GPX4), and long non-coding RNA (lncRNA). Therefore, m6A modification showed great promise as potential targets in CNS injuries. In this article, we present a review highlighting the role of m6A modification in CNS injuries. Hence, on the basis of these properties and effects, m6A modification may be developed as therapeutic agents for CNS injury patients.

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Comprehensive analysis of N6-methyladenosine (m6A) modification during the degeneration of lumbar intervertebral disc in mice

Cited by 13 publications

References 55 publications

Comprehensive analysis of m6A methylation modification in chronic spinal cord injury in mice

Comprehensive analysis of m6A methylation modification in chronic spinal cord injury in mice

M6A methylation‐regulated autophagy may be a new therapeutic target for intervertebral disc degeneration

Crosstalk among N6-methyladenosine modification and RNAs in central nervous system injuries

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