Functional analyses of super-enhancer dysregulation in colorectal carcinoma patient samples.

项目摘要 结直肠癌（CRC）是一种恶性肿瘤，其在癌症发病率和死亡率中都是最高的。 死亡率在美国男性和女性，但疾病仍然依赖于细胞毒性治疗， 标准的护理，强调需要确定新的目标。我们和其他团体 在CRC中表现出广泛的增强子重编程;然而，它们对疾病的生物学影响 进展仍然未知。使用组织ChIP-seq和RNA-seq方法对人类CRC肿瘤进行研究， 匹配正常上皮，我发现CRC中的增强子重编程延伸到超级增强子（SE） 景观纳入相同数量的患者匹配的正常结肠直肠隐窝上皮对照 鉴定了异常的肿瘤特异性超级增强子的从头形成以及生理活性的频繁丧失， 在我的样本队列中具有高复发率的正常特异性SE。超级增强子被很好地描述为 选择性调节关键细胞身份基因，包括恶性细胞中的原癌基因-它们的谱是一个 通过利用表观基因组，在许多难以治疗的癌症中建立了靶点发现框架 失调因此，我们的初步研究结果对CRC生物学具有独特的意义。在这份提案中，我寻求 以阐明CRC肿瘤中顶部反复获得和丢失的超级增强子的功能。我将测试 假设干扰SE和假定的调控基因将影响CRC的增殖和侵袭 使用体外和结肠类器官驱动的体内模型。拟议项目的结果将提前 在CRC肿瘤中的主动调节景观如何有助于肿瘤发生的领域中的知识， 促进研究和治疗靶向的新途径。

PROJECT SUMMARY Colorectal carcinoma (CRC) represents a malignancy that is among the highest in both cancer incidence and mortality in men and women in the United States, yet disease remains dependent on cytotoxic therapies as standard of care, highlighting a need for the identification of novel targets. We and other groups have demonstrated extensive enhancer reprogramming in CRC; however, their biological impact on disease progression remains unknown. Using a tissue ChIP-seq and RNA-seq approach on human CRC tumors and matched normal epithelium, I found that enhancer reprogramming in CRC extends to the super-enhancer (SE) landscape. The inclusion of an equal number of patient-matched normal colorectal crypt epithelium controls identifies de novo formation of aberrant, tumor-specific super-enhancers as well as frequent loss of physiologic normal-specific SEs with high recurrence across my cohort of samples. Super-enhancers are well-described to selectively regulate key cell identity genes including proto-oncogenes in malignant cells—their profiling is an established framework in target discovery in many difficult to treat cancers through leveraging epigenomic dysregulation. Thus, our preliminary findings have unique implications for CRC biology. In this proposal, I seek to elucidate a function for top recurrently gained and lost super-enhancers in CRC tumors. I will test the hypothesis that perturbing both SEs and putative regulated genes will affect proliferation and invasion in CRC using in vitro and colon organoid driven in vivo models. Findings from the proposed project will advance knowledge in the field of how the active regulatory landscape in CRC tumors contributes to tumorigenesis, promoting novel avenues of investigation and therapeutic targeting.