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，这为功能性基因组提供了背景。 核中的过程。最近的进展表明存在染色质区室，CTCF 环和小基因环作为基因组组织的普遍特征。我们的高分辨率调查 揭示了亚基因不一致区室的存在，将许多基因的5'和3'末端相对放置， 隔间状态。这些，沿着与基因环，是高度相关的转录延伸状态，但 转录如何影响这些亚基因结构是未知的。此外，这些空间位置 特征是基因组组织的一个重要方面，但在很大程度上被忽视了，这些特征中哪些是 取决于径向位置是不清楚的。我们研究的目的是确定 转录和亚基因尺度染色质组织，并阐明空间位置的影响， 染色质折叠我们将通过使用（1）基本的机械审讯来实现这些目标， 跟踪亚基因结构如何随着转录的进展而变化，（2）软件开发， 灵敏度和定量保真度在精细尺度区室分析，和（3）研究基因组学，以丰富 并定义染色质接触和径向位置之间的关系。结果 这项研究将解决围绕转录和基因折叠的机制问题， 需要和节省成本的工具进行精细规模的分析，并确定空间依赖的染色质组织。

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.