MECHANISMS OF DYNAMIC CHROMATIN LOOPING DURING DIFFERENTIATION

摘要 染色质环跨越数十到数百个千碱基连接启动子-远端调控元件，如 目的基因启动子的增强剂。其中许多环路是特定于细胞类型的，被认为是 在细胞分化和人类发育过程中起着关键的转录调控作用。近期 我们探测这些环的能力的进步极大地促进了我们对分子的了解 DNA环的组成；然而，细胞内DNA环变化的机制和功能 人们对它们的区别仍然知之甚少。我们研究的目标是通过 哪些细胞在细胞分化过程中建立新的环路，并确定所产生的结构如何 有助于改变转录输出。我们将通过以下方式实现这些目标：(1)映射循环，规范 事件，以及细胞分化过程中具有时间分辨率的基因转录，(2)发育和 应用新软件来识别和可视化动态循环事件，以及(3)执行有针对性的 对在分化过程中形成的环路的机械研究。这项研究的结果将决定 DNA环在分化过程中形成的范围和一般原理，为 基因调控社区，并阐明了非编码人类基因组的功能。

ABSTRACT Chromatin loops spanning tens to hundreds of kilobases link promoter-distal regulatory elements such as enhancers to the promoters of their target genes. Many of these loops are cell-type specific and are thought to play a critical role in transcriptional control during cellular differentiation and human development. Recent progress in our ability to detect these loops has significantly advanced our knowledge regarding the molecular components of DNA loops; however, the mechanisms and functions of changes in DNA looping during cellular differentiation remain poorly understood. The goals of our research are to identify the mechanisms through which cells establish new loops during cellular differentiation and to determine how the resulting structures contribute to altered transcriptional output. We will accomplish these goals by: (1) mapping loops, regulatory events, and gene transcription with temporal resolution during cellular differentiation, (2) developing and applying new software to identify and visualize dynamic looping events, and (3) performing targeted mechanistic investigations of loops formed during differentiation. The results of this research will determine both the scope and general principles of DNA loop formation during differentiation, provide new tools for the gene regulation community, and illuminate the functions of the non-coding human genome.