通过结合外源性BMAL1表达和多镇压复合体2抑制在人类诱导的多能干细胞中,人工诱导昼夜节律
Hitomi Kaneko1, Taku Kaitsuka2, Kazuhito Tomizawa3
1Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan.
Cellular and molecular life sciences : CMLS
|July 8, 2023
概括
人类诱导的多能干细胞 (iPSCs) 由于表观遗传沉默时钟基因而缺乏昼夜节律. 增强BMAL1和抑制EZH2恢复了这些干细胞中的昼夜基因表达.
科学领域:
- 干细胞生物学 干细胞生物学
- 时间生物学 时间生物学
- 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:
- 人类诱导的多能干细胞 (iPSC) 对再生医学至关重要,但与体细胞具有功能差异.
- 在iPSC中缺少的一个关键功能是时钟基因的昼夜振荡,这对于正常细胞的时间调节至关重要.
- 在iPSC中缺乏昼夜节律的潜在机制尚未完全理解.
研究的目的:
- 研究人类iPSC中昼夜节律缺失背后的原因.
- 探索基因组甲基化和BMAL1蛋白水平在调节时钟基因表达中的潜在作用.
- 确定恢复iPSCs昼夜功能的策略.
主要方法:
- 生成的人类iPSCs过度表达大脑和肌肉ARNT-like 1 (BMAL1).
- 用GSK126治疗的细胞,GSK126是一种增强剂增强剂的抑制剂,它是基因素甲基转移酶的zest同类物2 (EZH2).
- 监测BMAL1,2期 (PER2) 和其他时钟基因的表达.
主要成果:
- 过度表达BMAL1和抑制EZH2一起诱导iPSCs显著的昼夜节律.
- 观察到内源性BMAL1,PER2和其他关键时钟基因的节奏表达恢复.
- 这些发现表明一种涉及表观遗传调节和BMAL1水平的机制.
结论:
- 人类iPSC中缺乏昼夜节律可能源于通过H3K27高甲基化和低BMAL1水平的时钟基因的转录抑制.
- 调节BMAL1表达和EZH2活性可以恢复iPSCs的昼夜基因振荡.
- 这项研究提供了对iPSC生理学和再生医学潜在治疗点的见解.
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