细度结构信息大大改善了mRNA在瓶中的降解预测的多变量回归模型
bioRxiv : the preprint server for biology
|September 2, 2025
概括
优化信使RNA (mRNA) 的稳定性对于疫苗开发至关重要. 新的研究表明,局部RNA结构特征,特别是基配概率,显著改善了溶液中mRNA稳定性的预测.
科学领域:
- 生物化学
- 分子生物学
- 生物信息学
背景情况:
- COVID-19 mRNA 疫苗的有效性凸显出需要稳定的 mRNA 分子.
- 了解控制溶液中的mRNA稳定性的序列指标对于疫苗开发和储存至关重要.
- 目前用于预测mRNA稳定性的方法往往忽略了对降解抵抗至关重要的局部结构变异.
研究的目的:
- 确定影响溶液中的mRNA稳定性的关键序列指标.
- 通过结合本地结构特征,开发一个改进的mRNA稳定性预测模型.
- 增强mRNA分子的设计,以提高溶液中的稳定性.
主要方法:
- 对RNA二次结构及其与降解的相关性进行分析.
- 使用基数配对概率 (逻辑概率) 作为结构分析的微量度量.
- 开发一个结合全球和本地序列特征的回归模型 (STRAND).
主要成果:
- 当地结构特征,特别是基配概率,提供了超越全球指标的直角见解,例如最小自由能量.
- 综合四个关键特征的STRAND模型在预测mRNA稳定性方面显著优于现有的方法.
- STRAND为以稳定性为重点的mRNA设计提供了一个紧且可解释的框架.
结论:
- 基配概率是预测mRNA稳定性的关键,细度度指标.
- STRAND模型为设计更稳定的mRNA分子提供了一种实用且有效的方法.
- 通过更深入地了解局部结构决定因素,可以提高mRNA的稳定性.
相关概念视频
mRNA Stability and Gene Expression
5.7K
The structure and stability of mRNA molecules regulates gene expression, as mRNAs are a key step in the pathway from gene to protein. In eukaryotes, the half-life of mRNA varies from a few minutes up to several days. mRNA stability is essential in growth and development. The absence of the proteins regulating its stability, such as tristetraprolin in mice, can cause systemic issues, including bone marrow overgrowth, inflammation, and autoimmunity.
Cis-acting Elements involved in mRNA stability
Cis-acting Elements involved in mRNA stability
5.7K
Nuclear Export of mRNA
7.9K
Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
7.9K
RNA Stability
33.9K
Intact DNA strands can be found in fossils, while scientists sometimes struggle to keep RNA intact under laboratory conditions. The structural variations between RNA and DNA underlie the differences in their stability and longevity. Because DNA is double-stranded, it is inherently more stable. The single-stranded structure of RNA is less stable but also more flexible and can form weak internal bonds. Additionally, most RNAs in the cell are relatively short, while DNA can be up to 250 million...
33.9K
Regulation of Expression Occurs at Multiple Steps
23.2K
Gene expression can be regulated at almost every step from gene to protein. Transcription is the step that is most commonly regulated. This involves the binding of proteins to short regulatory sequences on the DNA. This association can either promote or inhibit the transcription of a gene associated with the respective sequence.
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...
23.2K
Regulation of Expression at Multiple Steps
994
The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
994
Nonsense-mediated mRNA Decay
10.8K
The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
10.8K


