H3K79甲基化和H3K36三甲基化协同调节多能干细胞中的基因表达
Emmalee W Cooke1, Cheng Zeng1,2, Suza Mohammad Nur1,2
1Department of Biochemistry, Case Western Reserve University.
bioRxiv : the preprint server for biology
|June 4, 2025
概括
基因组甲基化标记H3K79me和H3K36me3协同调节基因表达和神经细胞命运. 它们的丧失导致过度转录和差异化受损,揭示了新的治疗点.
科学领域:
- 表观遗传学和基因调控
- 发展生物学 发展生物学
- 分子瘤学分子瘤学
背景情况:
- 希斯甲基化,特别是DOT1L沉积的H3K79me,标记了metazoans中的活跃基因.
- DOT1L与人类疾病有关,但H3K79me的确切作用尚不清楚.
- H3K36me3是另一个活跃的基因标记,其与H3K79me的相互作用尚未探索.
研究的目的:
- 研究H3K79me和H3K36me3在基因表达和神经细胞命运中的协同作用.
- 阐明这些基因组修饰之间的功能相互作用背后的分子机制.
- 为涉及DOT1L和SETD2.2疾病的潜在治疗策略提供见解.
主要方法:
- 基因编辑同时禁用DOT1L和SETD2,删除H3K79me和H3K36me3.
- 全球基因表达,染色质可访问性和转录因子结合的分析 (YAP1-TEAD4).
- 对YAP-TEAD通路的药理抑制,以评估其对基因表达的影响.
主要成果:
- 同时失去H3K79me和H3K36me3导致全球超转录和神经分化失败.
- 这些标记的缺失增加了转录延长和提高了可访问性,促进了YAP1-TEAD4结合.
- 抑制YAP-TEAD信号传递在H3K79me/H3K36me3损失后部分挽救基因表达水平.
结论:
- H3K79me和H3K36me3协同作用,控制基因表达和神经细胞命运.
- 这种协同作用涉及对转录延长,增强剂活性和YAP1-TEAD信号的调节.
- 了解这种相互作用为治疗与DOT1L和SETD2功能障碍相关的疾病提供了新的途径.
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