1Kb分辨率Hi-C数据分析框架搭建及其在人干细胞肝向分化研究中的应用

Chromatin conformation refers to a structure in which a genome expands in a specific three-dimensional space. Chromatin conformation and its changes are closely related to gene expression regulation, DNA replication and other processes, and are crucial for determining cell fate. Hi-C technology has attracted attention and has been widely used because it can simultaneously detect the chromatin conformation in the whole genome level. With the mutual promotion and development of Hi-C technology and Hi-C data analysis methods, people's understanding of the chromatin conformation is increasingly refined. Recently, our group developed the high-resolution Hi-C detection technology, named as BL-Hi-C, which can make 1Kb resolution Hi-C data with about 640M reads. At the same time, the bioinformatics analysis methods for high-resolution, especially for 1Kb-resolution Hi-C data are still lacking or need to be improved. Therefore, this project we plan to develop 1Kb resolution Hi-C data analysis method based on the key issue of the changes of chromatin conformation, set up a 1Kb resolution Hi-C data analysis framework. In the framework the algorithms are linked logically and automatically. And then, we will apply the framework in the study of hepatic differentiation of human stem cells. Finally, we would hope these studies will help the development of bioinformatics tool for 3D Genomics.

染色质构象（chromatin conformation）是指基因组在特定三维空间中展开的结构。染色质构象及其变化与基因表达调控、基因组复制等过程密切相关，对决定细胞命运至关重要。Hi-C技术由于能同时检测全基因组范围上的染色质构象而备受重视和广泛使用。随着Hi-C技术和Hi-C数据分析方法的相互促进与发展，人们对染色质构象的认识也日益精细。最近本研究小组开发出高分辨率Hi-C技术BL-Hi-C，实现了仅用约640M reads就产生1Kb分辨率Hi-C数据的效果。而与此同时，高分辨率特别是1Kb分辨率Hi-C数据的生物信息学分析方法仍旧缺乏或有待完善。因此，本项目计划围绕染色质构象变化这一关键问题，发展1Kb分辨率Hi-C数据分析方法，搭建1Kb分辨率Hi-C数据分析框架，实现算法之间的有机关联与自动化衔接，完成该分析框架在人干细胞肝向分化研究中的应用，推动三维基因组学数据分析工具发展。

染色质构象及其变化与基因表达、复制等过程密切相关，对决定细胞命运至关重要。Hi-C技术能检测全基因组范围的染色质构象，在本项目启动时行业内仍缺少专门针对 1Kb 分辨率 Hi-C 数据的生物信息学处理流程。因此，通过本项目研究我们完成1Kb分辨率Hi-C数据分析框架搭建，进一步开发了基因组拓扑空间结构分析算法HiCDB、三维基因组密度空间分析算法SDOC、MINE等，并有效的将上述方法应用到人肝细胞分化过程中的三维基因组调控机理研究中，揭示了YAP分子介导的基因表达增强模式。同时我们还开发了业界首个组织水平单细胞代谢组技术SEAM，今后基因组空间结构的动态变化研究建立了基础。相关项目标注论文在Nature Methods、Nature Communications、Nucleic Acids Research、Genome Biology等国际一流期刊发表通讯/共同通讯作者论文11篇。成果入选2021年中国生物信息学十大进展。项目获批中国专利3项，在申中国专利1项。项目培养博士后1人（获第一届博新计划支持），培养博士研究生4名。