在六种人类癌症中,在2.8 Mb的拓相关域中,对cis-regulatory元素进行了全面的剖析
Christina M Caragine1,2,3,4, Victoria T Le1,2,3,4, Meer Mustafa1,2,3,4
1New York Genome Center, New York, NY, USA.
Nature communications
|February 13, 2025
概括
研究人员使用CRISPR抑制屏幕绘制了控制人类癌细胞MYC基因的cis调节元件 (CREs). 他们确定了32个增长调节CREs,揭示了对MYC表达和细胞增殖至关重要的关键调节区域.
科学领域:
- 基因组学就是基因组学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 像增强剂和促进剂这样的Cis-regulatory元素 (CREs) 对基因表达至关重要.
- MYC基因位点在不同细胞类型中表现出多样化的调节架构.
- 了解CRE功能对于破译各种细胞环境中的基因调节至关重要.
研究的目的:
- 在MYC拓关联域 (TAD) 中全面地绘制和功能性地描述CREs.
- 确定调节MYC表达并影响癌细胞生长的CREs.
- 研究CREs,MYC表达和癌症中转录因子结合之间的关系.
主要方法:
- 聚合CRISPR抑制 (CRISPRi) 屏幕在6个人类癌症细胞系的核酸分辨率下进行.
- 使用3D增强器接触映射来评估CREs和MYC基因之间的相互作用.
- 进行了相关性分析,以将转录因子 (TF) 表达与瘤和正常组织中的MYC表达联系起来.
主要成果:
- 在MYC TAD中确定了32个CREs,这些CREs在抑制时调节细胞生长.
- 针对特定的CRE降低了多达60%的MYC表达和多达50%的细胞生长.
- 发现MYC接触CREs的一个子集具有表型相关性,当沉默时会影响细胞生长.
结论:
- 系统地识别控制癌症中MYC的功能调节区域.
- 证明特定的CREs如何促进MYC驱动的细胞生长和癌症进展.
- 发现了转录因子和MYC表达之间的瘤特异性相关性,突出了潜在的治疗点.
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