Center for Integrated Multi-modal and Multi-scale Nucleome Research

转录调控序列在转录调控系统中动态地相互通信。 3D核空间指导细胞类型特异性基因表达。目前，一个主要的障碍， 理解转录调控程序是缺乏工具，模型和地图 探索不同细胞类型和生理背景下的染色质结构。我们 将通过部署变革性技术来研究 以前所未有的分辨率和规模研究哺乳动物细胞的染色质结构。 具体来说，我们将生成可导航的、细胞类型特异性的染色质参考图谱 在小鼠，猕猴和人类大脑的结构，通过整合高分辨率和 高通量成像和基于单细胞的正交基因组方法。我们还将 通过一组受控的染色体组， 在小鼠ES细胞（ESC）和ESC衍生的神经祖细胞中的扰动实验 细胞（NPC）。我们将开发染色质组织的结构模型， 聚合物物理和统计学习方法，并验证其预测能力， 胚胎干细胞和离体脑切片。最后，我们将制作参考地图， 分析工具、可视化方法和结构模型， 社区拟议中的研究项目将极大地改变我们分析 复杂组织的4D核组，并产生急需的地图，工具和 理解线性基因组中编码的基因调控程序的模型 序列的

The transcriptional regulatory sequences communicate with each other dynamically in the 3D nuclear space to direct cell type specific gene expression. Currently, a major barrier to understanding the transcriptional regulatory programs is the lack of tools, models and maps to explore the chromatin architecture in diverse cell types and physiological contexts. We will address this pressing need by deploying transformative technologies to study the chromatin architecture in mammalian cells at an unprecedented resolution and scale. Specifically, we will generate navigable, cell-type-specific reference maps of chromatin architecture in the mouse, macaque and human brains by integrating high resolution and high throughput imaging and orthogonal single-cell-based genomic methods. We will also dissect the role of chromatin architecture in gene regulation through a set of controlled perturbation experiments in the mouse ES cells (ESC) and ESC-derived neural progenitor cells (NPC). We will develop structural models of chromatin organization with advanced polymer physics and statistical learning methods, and validate their predictive power in embryonic stem cells and in ex vivo brain slices. Finally, we will make the reference maps, analytical tools, visualization methods and structural models available to the broader community. The proposed research project will dramatically transform our ability to analyze the 4D Nucleome of complex tissues, and produce the much-needed maps, tools and models for understanding the gene regulatory programs encoded in the linear genome sequences.