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

转录调控序列在转录调控序列中动态地相互通信 3D核空间来指导细胞类型特异性基因的表达。目前，一个主要的障碍是 理解转录调控计划缺乏工具、模型和地图 探索不同细胞类型和生理环境下的染色质结构。我们 将通过部署变革性技术来研究 哺乳动物细胞中的染色质结构以前所未有的分辨率和规模。 具体来说，我们将生成可导航的、特定于细胞类型的染色质参考图 在小鼠、猕猴和人脑中通过集成高分辨率和 高通量成像和基于单细胞的正交基因组方法。我们还将 通过一组对照研究，剖析染色质结构在基因调控中的作用 小鼠胚胎干细胞及其神经前体细胞的扰动实验 细胞(NPC)。我们将开发先进的染色质组织结构模型 聚合物物理和统计学习方法，并验证它们的预测能力 胚胎干细胞和体外脑片。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可供更广泛的 社区。拟议的研究项目将极大地改变我们的分析能力 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。

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.