现代基因组学研究结果表明，人类基因组中非编码调控序列的含量远远超过了编码序列。这些非编码调控序列包括启动子，增强子、沉默子和绝缘子等。这些序列被证明在个体发育和细胞分化过程中具有很重要的调节功能。比如，增强子能够结合细胞组织特异的转录因子，进而激活相应的启动子来建立细胞特有的转录程序。然而在过去很长一段时间，由于这些元素的非编码性，它们的检测和在基因组中的定位是比较困难的。近些年来的研究表明表观遗传标记能识别和区分编码和非编码调控元件。在过去的几年中，我们和其他实验室在人或小鼠的多种成熟组织和细胞系中鉴定了数十万非编码调控元件。然而，由于实验条件所限，类似的研究在早期胚胎发育中仍然是一个空白。早期胚胎发育时期是新的生命诞生的开始，在这个时期基因转录和染色体状态发生了剧烈的重编程。我们计划通过多种新的实验方法来检测并研究非编码调控元素以及染色体高级结构在哺乳动物早期胚胎发育中的功能。

Recent studies have shown that the mammalian genome includes a surprisingly large portion of non-coding cis-regulatory elements, including promoters, enhancers, silencers and insulators. These elements often play crucial roles in gene regulation in development and cell differentiation. For instance, enhancers can interact with lineage specific transcription factors and promoters to establish cell type-restricted transcription circuitry. However, the identification of cis-regulatory elements in the past remained a challenge due to their non-coding nature. Recent studies have discovered that epigenetic signatures can be used to identify the locations of these cis-regulatory elements. As a result, previous work from us and others have found hundreds of thousands of enhancers in tissues and cell lines in humans and mice. However, a large-scale functional study of cis-regulatory elements in preimplantation embryos, where the genome and chromatin undergo dramatic reprogramming, is still lacking. This is in part due to the limited numbers of cells that can be collected from these embryos. With several novel methods established in lab, we aim to identify the cis-regulatory elements in the genome of preimplantation embryos in mice. Further, we will study the roles of these elements and the higher order structure of chromatin in early mammalian development.

受精和早期胚胎发育标志着新生命的开始。具有单一功能的配子如何变成全能性胚胎是生命科学的核心问题之一。通过多学科交叉包括分子生物学、基因组学和发育生物学，本课题组致力于研究细胞分化和早期胚胎发育中表观遗传调控的模式、机制以及功能，以及鉴定早期胚胎发育过程中非编码调控序列并初步研究其功能。本课题组在基金支持下做出了多项开创性的工作，包括首次在分子水平研究哺乳动物生命起始时期染色体的动态调控并鉴定启动子和增强子等调控序列(Nature, 2016a)，及首次回答了组蛋白修饰是否能够在代间遗传的重大科学问题 (Nature, 2016b; Molecular Cell, 2016)，发现了小鼠早期胚胎发育过程中染色质三维结构重编程模式和调控机制 (Nature, 2017)以及首次系统研究了哺乳动物早期胚胎谱系分化过程中表观遗传信息建立模式及调控 (Nature Genetics, 2017)。这些工作展现了哺乳动物胚胎发育早期表观遗传信息的遗传、重编程和重建的模式与机理，寻找和研究了这个时期的非编码调控序列，极大地促进了人们对生命如何起始的理解。