DNMT1 Y495C突变干扰了印记控制区域的维护甲基化
Sumana Choudhury1, Anuhya Anne1, Minali Singh2
1Molecular Biology and Genetics Laboratory, Department of Biological Sciences, BITS Pilani Hyderabad Campus, Hyderabad 500078, India; Centre for Human Disease Research, BITS Pilani Hyderabad Campus, Hyderabad 500078, India.
The international journal of biochemistry & cell biology
|January 28, 2024
概括
一个新的DNA甲基转移酶1 (DNMT1) 突变导致遗传性感官和自主神经病变1E类型 (HSAN1E) 通过特别影响印记控制区域. 这导致基因失调和神经元发育异常.
科学领域:
- 遗传学 遗传学 是一个
- 神经科学是一个神经科学.
- 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:
- 遗传性感官和自主神经病变1E型 (HSAN1E) 是一种罕见的神经疾病,与DNA甲基转移酶1 (DNMT1) 突变有关.
- 在HSAN1E中具有主导作用的确切机制,特别是关于DNMT1在DNA甲基化中的作用,仍然不清楚.
研究的目的:
- 研究DNMT1突变 (Y495C) 对DNA甲基化模式的特定影响,重点研究印记控制区域 (ICR).
- 了解这种突变如何影响小鼠胚胎干细胞 (mESC) 和发育中的神经元中的基因表达和细胞特征.
主要方法:
- 野生型 (R1) 和突变型 (R1Dnmt1Y495C) mESCs过度表达DNMT1变体中的甲基组的比较.
- 在mESC和衍生神经元中印制基因的转录水平的分析.
- 评估来自突变细胞的神经元中的细胞形态和分化标志物.
主要成果:
- R1Dnmt1Y495C细胞在20个印记控制区域 (ICR) 中15个表现出低甲基化.
- 在ESC和神经元中,在转录水平上观察到多个印记基因的失调.
- 来自R1Dnmt1Y495C细胞的神经元显示出改变的形态,看起来更苗条,更短,并增加了分支.
结论:
- DNMT1 Y495C突变特别针对和低甲基化印记控制区域 (ICRs),使其与其他甲基化效应区别开来.
- 这种特定的低甲基化导致对发育至关重要的印记基因的失调,影响神经发生并导致HSAN1E.
- 这些发现表明,突变DNMT1蛋白质二极体可能会在早期发育过程中导致ICR甲基化逐渐丧失.
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