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

项目总结 结直肠癌(CRC)是一种癌症发病率最高的恶性肿瘤。 在美国，男性和女性的死亡率，然而疾病仍然依赖于细胞毒疗法，因为 护理标准，强调需要确定新的目标。我们和其他团体有 在结直肠癌中显示了广泛的增强子重新编程；然而，它们对疾病的生物学影响 进展情况尚不清楚。用组织芯片-SEQ和RNA-SEQ方法治疗人结直肠癌和 匹配正常上皮，我发现结直肠癌的增强子重新编程延伸到超级增强子(SE) 风景。纳入相同数量的患者匹配的正常结直肠隐窝上皮对照 识别异常的、肿瘤特异性的超级增强子的从头形成以及频繁的生理性丧失 在我的样本队列中有高复发率的正常特异性SES。超级增强剂被很好地描述为 选择性地调控关键细胞识别基因，包括恶性细胞中的原癌基因-它们的特征是 通过利用表观基因组在许多难以治疗的癌症中发现靶点的框架 监管失调。因此，我们的初步发现对结直肠癌生物学具有独特的意义。在这项提议中，我寻求 目的：阐明TOP重复获得和丢失的超级增强子在结直肠癌中的作用。我会测试一下 SES和可能的调控基因同时干扰会影响结直肠癌增殖和侵袭的假说 采用体外和结肠类有机物驱动的体内模型。拟议项目的调查结果将会取得进展 关于结直肠癌中活跃的调控格局如何促进肿瘤发生的领域知识， 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.