Dynamics of N6-methyladenosine modification during aging and their potential roles in the degeneration of intervertebral disc

IF 3.4 3区医学 Q1 ORTHOPEDICS JOR Spine Pub Date : 2024-01-25 DOI:10.1002/jsp2.1316

Libangxi Liu, Hong Sun, Yang Zhang, Chang Liu, Yong Zhuang, Miao Liu, Xuezheng Ai, Dan Long, Bo Huang, Changqing Li, Yue Zhou, Shiwu Dong, Chencheng Feng

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Abstract

Background

The N6-methyladenosine (m6A) dynamics in the progression of intervertebral disc (IVD) aging remain largely unknown. This study aimed to explore the distribution and pattern of m⁶A modification in nucleus pulpous (NP) tissues of rats at different ages.

Methods

Histological staining and MRI were performed to evaluate the degeneration of IVD. The expression of m6A modifiers was analyzed using qRT-PCR and western blot. Subsequently, methylated RNA immunoprecipitation next generation sequencing and RNA-seq were conducted to identify differences in m6A methylome and transcriptome of NP tissues.

Results

Compared to 2-month-old rats, we found significant changes in the global m6A level and the expression of Mettl3 and FTO in NP tissues from 20-month-old rats. During the progression of NP aging, there were 1126 persistently differentially m6A peaks within 931 genes, and 51 persistently differentially expressed genes. GO and KEGG analyses showed that these m6A peaks and m6A modified genes were mainly engaged in the biological processes and pathways of intervertebral disc degermation (IDD), such as extracellular matrix metabolism, angiogenesis, inflammatory response, mTOR and AMPK signaling pathways. Meanwhile, conjoint analyses and Venn diagram revealed a total of 405 aging related genes contained significant methylation and expression levels in 20-month-old rats in contrast to 2-month-old and 10-month-old rats. Moreover, it was found that four aging related genes with hypermethylated modification including BUB1, CA12, Adamts1, and Adamts4 depicted differentially expressed at protein level, of which BUB1 and CA12 were decreased, while Adamts1 and Adamts4 were increased during the progression of NP aging.

Conclusion

Collectively, this study elucidated the distribution and pattern of m6A modification during the aging of IVD. Furthermore, the m6A modified genes were involved in the IDD related biological processes and pathways. These findings may provide novel insights into the mechanisms and therapies of IDD from the perspective of aging.

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老化过程中 N6-甲基腺苷修饰的动态变化及其在椎间盘退化中的潜在作用。

背景：N6-甲基腺苷（m6A）在椎间盘（IVD）老化过程中的动态变化在很大程度上仍是未知的。本研究旨在探讨不同年龄大鼠髓核组织中 m6A 修饰物的分布和模式。采用 qRT-PCR 和 Western 印迹法分析 m6A修饰物的表达。随后，进行了甲基化 RNA 免疫沉淀新一代测序和 RNA-seq 分析，以确定 NP 组织中 m6A 甲基组和转录组的差异：结果：与 2 月龄大鼠相比，我们发现 20 月龄大鼠 NP 组织中 m6A 的整体水平以及 Mettl3 和 FTO 的表达均发生了显著变化。在NP衰老过程中，931个基因中有1126个持续差异m6A峰，51个持续差异表达基因。GO和KEGG分析表明，这些m6A峰和m6A修饰基因主要参与椎间盘退化（IDD）的生物学过程和通路，如细胞外基质代谢、血管生成、炎症反应、mTOR和AMPK信号通路等。同时，联合分析和维恩图显示，20月龄大鼠与2月龄和10月龄大鼠相比，共有405个衰老相关基因含有显著的甲基化和表达水平。此外，研究还发现，BUB1、CA12、Adamts1和Adamts4等4个存在高甲基化修饰的衰老相关基因在蛋白水平上存在差异表达，其中BUB1和CA12在NP衰老过程中表达量减少，而Adamts1和Adamts4在NP衰老过程中表达量增加：总之，本研究阐明了 IVD 衰老过程中 m6A 修饰的分布和模式。此外，m6A修饰基因参与了IDD相关的生物学过程和通路。这些发现可能会从衰老的角度为 IDD 的机制和治疗提供新的见解。

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