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远程发育增强剂集群的表观遗传重编程导致乳腺癌和肺腺癌中的SOX2过度表达
Luis E Abatti1, Patricia Lado-Fernández2,3, Linh Huynh4
1Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada.
Nucleic acids research
|September 22, 2023
概括
异常激活的发育增强剂通过破坏SOX2瘤基因表达来驱动癌症. 这种调节机制的重编程对于乳腺癌和肺腺癌的发展至关重要.
科学领域:
- * 分子生物学 * 分子生物学
- * 发育生物学 发育生物学
- * 癌症研究研究
背景情况:
- *增强器重编程与癌症的发展有关,但机制尚不清楚.
- *发育增强剂的异常激活可能导致瘤的转录失调.
研究的目的:
- * 识别和描述参与瘤发生的增强剂元素.
- *阐明乳腺癌和肺腺癌中增强剂重编程的分子机制.
- * 调查特定的转录因子在调节增强剂活性中的作用.
主要方法:
- *鉴定了一种在癌症中异常激活的增强剂集群 (SRR124-134).
- *在癌细胞中通过CRISPR中介删除增强剂集群.
- *对基因表达,全基因组转录和染色质可访问性的分析.
- *对转录因子结合和活性 (FOXA1,NFIB) 的研究.
- * 用小鼠模型进行研究,以评估发育中的角色.
主要成果:
- *删除SRR124-134集群会破坏SOX2瘤基因表达,并破坏全基因组转录和染色质可访问性的调节.
- * 破坏增强剂活性的癌细胞在体外表现出减少的殖民地形成.
- *SRR124-134集群中的染色质可访问性与原发性乳腺和肺瘤中的SOX2过度表达相关.
- *FOXA1作为激活剂,NFIB作为SRR124-134活动和SOX2转录的抑制剂.
- *在小鼠中,SRR124和SRR134区域的同胞性删除会导致致命的食道-气管分离缺陷.
结论:
- * 发育增强剂可以在瘤发生过程中被重新编程,从而促进癌症的进展.
- *SRR124-134增强剂集群在SOX2调节和癌细胞活力方面发挥着关键作用.
- *FOXA1和NFIB调解癌症中发育增强剂的异常激活.
- *了解发育和疾病期间的增强剂动态对于治疗策略至关重要.
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