Linking Maintenance of Chromosome Structure to Transcriptional Regulation

描述(申请人提供)：精确调控细胞中的基因表达是一项重要的任务，只有通过多个分子途径的协调才能完成。其中一个途径涉及到染色体结构成分对转录的调节。染色体结构的异常控制与各种发育综合征、畸形和由于基因调控不当而导致的肿瘤进展有关。最近的证据表明，在增强子环介导的转录过程中，通过DNA环的形成使增强子靠近启动子，从而将染色体结构与基因表达联系起来。干细胞是分析转录调控的理想细胞类型，因为其独特的能力可以分化为任何细胞类型的有机体，也可以自我更新。为了研究调控基因组转录的分子过程，我们将使用高通量的基于基因组的技术和方法。这项拟议的研究的目的是了解凝聚素在调节转录中的作用，凝聚素是维持染色体结构所需的一种蛋白质复合体。我们将绘制凝聚素在基因组上的分布图，并确定凝聚素招募和分布的相关因素。我们将研究凝聚素与转录装置的其他已知成员在全基因组中的占据模式，并将这种模式与基因表达数据相关联。揭示染色体结构在转录中的功能在很大程度上仍然是一个未被探索的研究领域，应该被认为是充分认识影响细胞中基因表达程序的各种过程之间的相互作用的关键。

DESCRIPTION (provided by applicant): The precise regulation of gene expression in the cell is an important task only accomplished by the coordination of multiple molecular pathways. One of these pathways involves the regulation of transcription by chromosome structural components. Aberrant control of chromosome structure is associated with a variety of developmental syndromes, deformities, and the progression of tumors due to the misregulation of genes. Recent evidence has linked chromosome structure to gene expression via the formation of DNA loops that bring enhancers in proximity to promoters during enhancer-loop-mediated transcription. Stem cells represent an ideal cell type to dissect transcriptional regulation due to their unique abilities to differentiate into any cell type of an organism, and alo self-renew. To study the molecular processes regulating transcription of the genome we will employ high-throughput genomic-based technologies and methodologies. The objective of this proposed research is to understand the role of Condensin, a protein complex required for the structural maintenance of chromosomes, in mediating transcription. We will map the distribution of Condensin on the genome and we will identify factors responsible for recruitment and distribution of Condensin. We will examine the pattern of genome-wide occupancy of Condensin with other known members of the transcriptional apparatus and also correlate this pattern with gene expression data. Uncovering the function of chromosome structure in transcription remains a largely unexplored area of research and should be considered essential in fully appreciating the interplay between the various processes that influence gene expression programs in the cell.