一种转录增强剂调节心脏成熟的过程
Myo Htet1, Shunyao Lei2, Sheetal Bajpayi1
1Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
Nature cardiovascular research
|August 28, 2024
概括
一个关键的心脏基因增强剂对于心肌细胞成熟和心脏功能至关重要. 它的破坏会损害发育并促进疾病,但有针对性的激活可以增强成熟.
科学领域:
- 心脏病学 心脏病学
- 分子生物学分子生物学
- 干细胞生物学 干细胞生物学
背景情况:
- 心肌细胞成熟对于成人心脏功能和人类多能干细胞衍生心肌细胞 (hPSC-CMs) 的使用至关重要.
- 准确的调节机制,特别是控制心肌细胞成熟及其与心脏病的联系的cis-regulatory元素水平,尚未完全理解.
- 在心肌细胞成熟期间,α-actinin 2 (ACTN2) 表达增加,这表明其调节元素很重要.
研究的目的:
- 研究一种保存的ACTN2增强剂在心肌细胞成熟和心脏功能中的作用.
- 探索ACTN2增强器功能障碍对心脏病机制的影响.
- 评估调节这种增强剂在hPSC-CMs中的治疗益处的潜力.
主要方法:
- 利用人类多能干细胞 (hPSC) 和小鼠模型来研究ACTN2增强剂.
- 生成的异构的ACTN2增强剂删除模型.
- 进行了转录基因分析 (体外和体内).
- 使用增强器CRISPR激活 (enCRISPRa) 来准ACTN2增强器.
主要成果:
- 对ACTN2增强体的异构除导致心肌细胞形态异常,心脏功能减弱和线粒体呼吸功能受损.
- 转录组分析揭示了心肌细胞成熟途径的破坏和拉巴胺素 (mTOR) 信号传递的哺乳动物目标的上调,导致衰老.
- 删除ACTN2增强剂增加了热冲击蛋白90A的表达,这是mTOR激活的媒介.
- 增强器ACTN2增强器的CRISPR激活成功促进了hPSC-CM成熟.
结论:
- 一种特定的转录增强剂在调节心脏成熟和心肌细胞生理学方面发挥着关键作用.
- 这种增强剂的失调有助于心脏功能障碍和疾病表型,通过影响mTOR信号和促进衰老.
- 准这种增强剂为调节心肌细胞成熟和治疗心脏病提供了潜在的策略.
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