Fine-Scale Genome Folding Relative to Transcription and Location

摘要 人类基因组被精确地折叠成各种结构，这为功能 核内的过程。最近的进展表明，染色质隔间的存在，CTCF 环和小基因环是基因组组织的普遍特征。我们以高分辨率进行的调查 揭示了亚基因不协调间隔的存在，将许多基因的5‘和3’端放置在相反的位置 车厢状态。这些基因和基因环与转录延伸状态高度相关，但是 转录如何影响这些亚基因结构尚不清楚。此外，这些区域的空间位置 特征是基因组组织的一个很大程度上被忽视的重要方面，这些特征中的哪些是 是否依赖于径向位置尚不清楚。我们研究的目标是确定 转录和亚基因尺度染色质组织以及阐明空间位置对染色质组织的影响 染色质折叠。我们将在使用(1)基本机械审讯的程序中实现这些目标 跟踪亚基因结构如何随着转录的进展而变化，(2)软件开发 精细间隔分析的灵敏度和定量保真度，以及(3)研究基因组学以丰富 用于外周相互作用，并定义染色质接触和径向位置之间的关系。结果是 这项研究将解决围绕转录和基因折叠的机制问题，提供新的全新的 所需和节省成本的工具，用于精细分析，并确定空间相关的染色质组织。

ABSTRACT The human genome is precisely folded into various structures, which provides the context for functional processes in the nucleus. Recent advances have indicated the presence of chromatin compartments, CTCF loops, and small gene-loops as prevalent features of genome organization. Our investigations at high resolution reveal the presence of sub-genic discordant compartments, placing the 5’ and 3’ ends of many genes in opposite compartment states. These, along with gene-loops, are highly correlated with transcription elongation status, but how transcription influences these sub-genic structures is unknown. Additionally, the spatial location of these features is an important aspect of genome organization that is largely ignored, and which of these features are dependent on radial location is unclear. The goals of our research are to determine the relationship between transcription and sub-genic scale chromatin organization and to elucidate the impact of spatial location on chromatin folding. We will accomplish these goals in programs that use (1) basic mechanistic interrogation to track how sub-genic structures change as transcription progresses, (2) software development for increased sensitivity and quantitative fidelity in fine-scale compartment analysis, and (3) investigative genomics to enrich for peripheral interactions and define the relationship between chromatin contacts and radial position. The results of this research will resolve mechanistic questions surrounding transcription and gene folding, provide new sorely needed and cost-saving tools for fine-scale analysis, and identify spatially dependent chromatin organization.