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人环素诱导心肌细胞染色质可访问性的全球变化,这些变化与心血管疾病的位置重叠
E Renee Matthews1, Raodatullah O Abodunrin2, John D Hurley3
1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
PLoS genetics
|October 14, 2025
概括
在乳腺癌治疗中使用的抗环素 (AC) 改变了心细胞染色质的可访问性,这可能解释了心血管疾病风险,如心房动 (AF) 和心力衰竭 (HF). 特拉斯图祖马布没有表现出这些影响.
科学领域:
- 基因组学就是基因组学.
- 心脏病学 心脏病学
- 药理学 药理学是指药理学的学科.
背景情况:
- 乳腺癌治疗方法,如 antracyclines (AC) 和Trastuzumab,与心血管疾病 (CVD) 有关,包括心房动 (AF) 和心力衰竭 (HF).
- 非编码基因变异与心血管疾病有关,但它们对心脏毒性癌症药物的调节反应尚不清楚.
研究的目的:
- 调查ACs和trastuzumab如何影响心脏细胞非编码基因组中的染色质可访问性.
- 确定心脏基因组中对这些癌症药物有反应的调节区域,并携带心血管疾病风险位置.
主要方法:
- 全球染色体可访问性测量了IPSC衍生的心肌细胞,这些心肌细胞接受了ACs (多克索鲁比,埃皮鲁比,多诺鲁比,米托克桑) 和Trastuzumab治疗3小时和24小时.
- 分析的重点是随着时间的推移对药物治疗的反应的差异性可访问性,并与已知与心血管疾病相关的遗传变异重叠.
主要成果:
- 抗逆转基因治疗诱导了染色质可访问性的广泛变化,特别是在早期的促进子近位区域和晚些时候的抗逆转基因响应基因附近.
- 晚期AC响应区域被丰富为FOS:JUNB转录因子基因,并与与AC诱导的心脏毒性,AF和HF相关的单核酸多态 (SNP) 叠加.
- 一种特定的AF/HF相关的SNP (rs3176326) 在响应ACs时显示染色质可访问性,基因素乙化和CDKN1A表达的增加.
结论:
- ACs会导致心肌细胞染色质可访问性的显著,时间依赖的变化,影响与心血管疾病风险变异相关的调节区域.
- 这些发现提供了一个分子机制,将AC治疗与AF和HF的遗传倾向联系起来.
- 药物反应性染色体区域可以帮助注释癌症患者心血管疾病风险分层的变异.
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