在急性髓性白血病中特定于亚型的3D基因组改变
Jie Xu1,2, Fan Song1,3, Huijue Lyu1
1Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Nature
|October 26, 2022
概括
这项研究揭示了急性髓性白血病 (AML) 突变如何改变3D基因组结构,确定了驱动癌症生长和基因表达变化的特定DNA元素和循环.
科学领域:
- 基因组学
- 癌症生物学
- 表观遗传学
背景情况:
- 急性髓性白血病 (AML) 是一种复杂的血液癌症,其特征是基因突变.
- 3D基因组结构改变在AML发病过程中的作用在很大程度上是未知的.
研究的目的:
- 研究AML相关突变对3D染色体结构的影响.
- 确定有助于反洗钱发展和发展的新型监管要素和循环.
主要方法:
- 在AML患者样本和健康捐赠者身上进行全基因组测序.
- 对表观遗传标记进行RNA测序,ATAC-seq和CUT&Tag (CTCF,H3K27ac,H3K27me3).
- 基于CRISPR的功能验证和全基因组二硫酸盐测序.
主要成果:
- 在AML中确定了A/B区,TAD和染色蛋白环的复发性和亚型特异性变化.
- 发现AML特异性促进剂-增强剂和促进剂-抑制剂循环,在基因调节中具有验证的作用.
- 发现结构变异诱导的增强器劫持和沉默器劫持事件影响AML细胞生长和基因表达.
结论:
- 三维基因组改变是急性髓性白血病的重要驱动因素.
- 抑制循环和被劫持的 cis-regulatory 元素代表了AML的潜在治疗目标.
- 在AML中,DNA甲基化,CTCF结合和3D基因组结构是复杂的联系和操作.
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