Reducing Cancer Transcriptional Heterogeneity through Regulation of Chromatin Structure

项目总结 癌变涉及复杂相互作用的突变和转录失调。 成百上千个基因。目前，还没有一个平台允许对这么多 基因同时存在。基因转录受到许多机制的调节，包括研究得很好的 组蛋白修饰和基因组区划机制以及仍存在的不足 了解染色质中复杂的物理纳米环境的作用。因为转录分子 相互作用是化学反应，它们取决于染色质内的局部物理环境 这反过来又取决于核小体以上长度尺度上染色质折叠的物理模式。这个 这个项目的首要目标是开发新的工具来调节整个染色质纳米环境- 癌症预防和治疗的大规模转录工程。转录多样性起到了 通过允许癌细胞探索它们的基因组空间而在癌症发生中发挥重要作用，并已被证明 促进癌细胞对化疗产生抗药性。该项目将利用以下方法 生物工程，以开发新的工具，以物理化学方式调节染色质结构， 受约束且适应性较差的状态。该项目将确定可以作为目标的物理化学机制。 为了减少转录异质性并验证染色质折叠标准化在患者中的有效性- 来源异种移植(PDX)结肠癌模型作为缓解化疗耐药的辅助治疗 通过降低肿瘤的转录异质性。

PROJECT SUMMARY Carcinogenesis involves the dysregulation, both mutational and transcriptional, of the complex interactions of hundreds of genes. Currently no platform allows for the predictable transcriptional modulation of this many genes simultaneously. Gene transcription is modulated by a number of mechanisms including the well-studied histone modification and genome compartmentalization mechanisms as well as the still insufficiently understood role of the complex physical nanoenvironment within chromatin. Since transcriptional molecular interactions are chemical reactions, they depend on the local physical environment within the chromatin which, in turn, depends on the physical pattern of chromatin folding at supra-nucleosomal length scales. The overarching goal of this project is to develop new tools to modulate the chromatin nanoenvironment for whole- scale transcriptional engineering for cancer prevention and therapeutics. Transcriptional diversity plays a major role in carcinogenesis by allowing cancer cells to explore their genomic space and has been shown to foster the emergence of resistance to chemotherapy in cancer cells. The project will leverage the methods of bioengineering to develop new tools to physico-chemically regulate chromatin structure toward a normalized, constrained, and less-adaptive state. The project will identify physico-chemical mechanisms that can be targeted to reduce transcriptional heterogeneity and validate the efficacy of the chromatin folding-normalization in patient- derived xenograft (PDX) tumor models of colon cancer as an adjuvant therapy for alleviating chemoresistance through the reduction of the transcriptional heterogeneity of tumors.