删除一个进化保存的TAD边界会影响小鼠的精子生成
bioRxiv : the preprint server for biology
|July 19, 2024
概括
在小鼠中破坏基因边界损害了精子生产和丸基因表达,显示非编码突变影响男性生育能力. 这凸显了在男性不孕症病例中研究非编码DNA的必要性.
科学领域:
- 遗传学 遗传学是一种遗传学.
- 生殖生物学 生殖生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 精子生成对男性生育能力至关重要,但可以因遗传和表观遗传变化而受到干扰.
- 虽然蛋白质编码突变与男性不孕症有关,但非编码突变的作用在很大程度上是未知的.
- 拓相关域 (TAD) 边界在基因调节中起作用.
研究的目的:
- 为了研究非编码突变对精子生成的影响.
- 评估破坏TAD边界对男性生殖功能的影响.
主要方法:
- 在Dmrtb1和Lrp8基因附近确定了一个保存的TAD边界.
- 使用CRISPR-Cas9删除TAD边界的26kb,包括CTCF结合点,在小鼠中.
- 进行了ChIP-seq和Hi-C以确认删除和改变的DNA相互作用.
- 分析丸基因表达,组织学,精子生产和突变小鼠的生育能力.
主要成果:
- CRISPR-Cas9删除成功删除了CTCF部位,并增加了跨TAD边界的DNA相互作用.
- 突变小鼠在丸基因表达和异常的丸组织学方面表现出显著的变化.
- 观察到精子生成效率下降了35%,每日精子产量下降了28%.
- 尽管精子产量减少,但突变小鼠的生育能力没有显著下降.
结论:
- 破坏TAD边界会对精子生产和丸基因调节产生负面影响.
- 影响基因调节的非编码突变可能对生育能力的影响小于编码突变.
- 在男性不孕症的病因分析中,应考虑非编码突变.
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