增强剂中的遗传变异改变心肌病基因表达和进展
Anthony M Gacita1, Dominic E Fullenkamp1, Joyce Ohiri1
1Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.M.G., D.E.F., J.O., T.P., M.J.P., E.M.M.).
Circulation
|January 22, 2021
概括
控制心肌病基因的基因变异,如MYH7和LMNA,会影响疾病的进展. 识别这些非编码变异剂为遗传性和非遗传性心肌病提供了新的见解.
科学领域:
- 心血管遗传学
- 表观遗传学
- 分子心脏病学
背景情况:
- 心肌病的表型因遗传和非遗传因素而异,基因表达受促进剂和增强剂的调节.
- 这些调节元件的人类遗传变异可能解释心肌病进展和结果的观察变异性.
研究的目的:
- 识别和功能验证心肌病基因MYH7和LMNA的增强剂.
- 研究增强剂中的基因组变异在心肌病进展中的作用.
主要方法:
- 使用表观基因分析,包括促进体捕获染色体构成,以确定MYH7和LMNA的增强剂.
- 在人类诱导的多能干细胞衍生的心肌细胞中验证了增强剂的功能.
- 全基因组分析发现了可能影响心脏基因表达的增强剂变异,其中一种变异与生物库数据的心肌病进展相关.
主要成果:
- 确定并验证了LMNA和MYH7的多种增强剂,其中包括一种调节MYH6到MYH7的表达切换剂.
- 在工程心脏组织中,关键增强剂的删除增加了MYH6表达和收缩率.
- 在MYH7附近的增强剂中发现了破坏转录因子结合部位的特定变异 (rs875908);基因编辑减少了MYH7的表达,这种变异与心肌病的进展有关.
结论:
- 增强剂在调节心肌病基因表达方面起着至关重要的作用.
- 增强器区域内的基因组变异与心肌病的进展有关.
- 这种综合方法成功地发现了适用于其他心脏基因的心肌病非编码修饰剂.
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