密码密度和招募的增强剂是肠道瘤开始的基础
Liam Gaynor1,2, Harshabad Singh1,3, Guodong Tie1
1Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
Nature
|January 8, 2025
概括
结直肠癌腺瘤需要邻近的突变肠道密室, 不仅仅是Apc突变. 这些合作细胞的特定增强剂可访问性推动了早期瘤的发展.
科学领域:
- 胃肠病学
- 癌症生物学
- 遗传学
背景情况:
- 在结直肠癌发病之前, 在健康的肠道中可能存在瘤突变.
- Apc突变激活Wnt信号,为肠道干细胞 (ISC) 提供增长优势.
- 目前尚不清楚不同来源的ISC是否同样形成瘤,以及瘤发生过程中 cis调节元素的变化.
研究的目的:
- 调查单独的Apc突变是否足以在没有受伤的肠道中形成腺瘤.
- 确定突变肠道密室在腺瘤发展中的作用.
- 在Wnt过度激活和瘤进展时探索cis调节元件的调节.
主要方法:
- 利用两种小鼠模型研究肠道干细胞中的APC删除.
- 评估了密度和聚合对腺瘤形成的影响.
- 使用ATAC-seq分析了具有或没有腺瘤关联的Apc突变ISC中增强剂的染色质可访问性.
主要成果:
- 腺瘤形成不是APC删除的必需结果,但需要靠近突变的肠道密室.
- 降低密度抑制了腺瘤的形成,而突变密度增加了它.
- 腺瘤常驻的ISC表现出数千种增强剂的开放色素,与不形成腺瘤的Apc-nullISC不同.
结论:
- 邻近的突变肠道密室之间的合作对于早期结直肠瘤产生至关重要.
- 增加特定增强剂的可访问性是腺瘤发展的关键事件,使腺瘤选择性基因活动成为可能.
- 随着其他致癌突变的积累,这些增强剂变化持续存在,突出显示了它们的早期作用.
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