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通过体外TFAM的线粒体DNA拷贝数减少,通过淘汰重塑核表观基因组和转录基因组

Julia Nguyen¹, Phyo W Win¹, Tyler Shin Nagano¹

¹Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

bioRxiv : the preprint server for biology

|February 14, 2024

概括

线粒体DNA拷贝数 (mtDNA-CN) 的减少会影响核DNA甲基化和基因表达. 这揭示了共享的基因和途径,将mtDNA-CN与衰老和慢性疾病联系起来.

科学领域:

基因组学和表观遗传学
细胞生物学细胞生物学
分子医学是分子医学.

背景情况:

线粒体DNA拷贝数 (mtDNA-CN) 与与年龄相关的疾病和死亡率有关.
了解mtDNA-CN和核DNA (nDNA) 之间的相互作用对于疾病洞察至关重要.

研究的目的:

调查减少mtDNA-CN如何影响核DNA甲基化和基因表达.
确定共享的基因和生物途径,调解mtDNA-CN对疾病的影响.

主要方法:

从减少mtDNA-CN (TFAM异构体淘汰) 和对照线的HEK293T细胞系生成表观基因组和转录基因组概况.
使用CRISPR-Cas9技术创建细胞系模型.
进行了甲基化和基因表达数据的综合分析.

主要成果:

确定了4242个不同的甲基化位点,228个不同的甲基化区域和179个与mtDNA-CN.CN相关的不同表达基因.
通过综合分析发现了381个基因-CpG对.
发现GABAergic通路,神经活性联体受体相互作用和ABCD1/2基因活性的过度表现.

结论:

线粒体DNA变异向核表观基因组和转录基因组发出信号.
染色质状态可能调节mtDNA-CN对基因表达的影响.
这些发现提供了有关发育,衰老和复杂疾病的机制的见解.

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