Feng Lab

The human genome is folded into hierarchical three-dimensional (3D) organization, which can be dissected into multiple levels. The development of chromosome conformation capture (3C) assay and its variants, including Hi-C , HiChIP and chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) , and others, have greatly expanded our knowledge of 3D genomic organization. At the large scale, megabase-scale A/B compartments segregate the genome into activating (A) and inactivating (B) regions . At the submegabase scale, contact domains represent regions of the genome that interact more frequently with themselves than with neighboring regions , serving as fundamental units of genome organization that constrain enhancer-promoter interactions. Chromatin loops bring distant regulatory elements such as enhancers and promoters into close proximity.
These complex three-dimensional high-level structures play extremely important roles in gene transcription regulation, development and disease occurrence, and are currently one of the most cutting-edge directions in biomedical research. Revealing the spatial arrangement and dynamic interactions of chromatin in the cell nucleus through three-dimensional genomics provides new perspectives for the study of gene expression regulation and the discovery of novel drug targets.

We published the first high-precision three-dimensional genomic map of human DCM and normal heart (H3K27ac HiChIP) and combined Hi-C, ChIP-seq, ATAC-seq, RNA-seq and other multi-omics data, which revealed the role of chromatin three-dimensional structural remodeling in the occurrence of DCM, and provided a new target for the future control of DCM and heart failure and the The study is of the following significance.The important findings of this study are as follows: i) A large number of aberrant enhancer-promoter interactions exist in DCM and are significantly associated with the upregulation of early cardiac developmental gene transcription; a class of non-transcribing promoters never reported in the past can act as enhancers to regulate the transcription of DCM-specific genes. ii) The enhancer/promoter regions of DCM-specific interactions have ATAC-seq regions, which can be used for the transcription of DCM genes. iii) The ATAC-seq region of DCM is a region of DCM that can be used for the regulation of DCM. (ii) The ATAC-seq signals of the DCM-specific enhancer/promoter regions were not significantly changed, which further suggested that DCM-specific gene transcription was not achieved by regulating chromatin openness, but by regulating remote chromatin interactions. iii) HAND1 was significantly enriched in the enhancer/promoter regions of the DCM-specific interactions, and overexpression of HAND1 induced enhancer-promoter interactions of cardiac developmental genes and the formation of DCM phenotype. iv) HAND1 was significantly enriched in the DCM-specific enhancer/promoter regions.

Under the guidance of Prof. Yijun Ruan (a pioneer in the field of 3D genome, former Director of Genome Science Department of Jackson Laboratory, and now Principal Investigator of Institute of Life Sciences, Zhejiang University), we have established a new generation of chromatin 3D genome structure capture technology, In-situ ChIA-PET, together with Dr. Ping Wang (now Research Associate Professor of Northwestern University), etc. Compared with the previous ChIA-PET method established by Prof. Ruan, the amount of cells required has been reduced by nearly 40 times (from 2x10 8 to 5x10 6), and the data quality has been greatly improved, which is of great significance for the analysis of 3D genome structure of primary cells.

We also participated in the establishment of ChIA-PIPE, a data analysis process forin situ ChIA-PET . Subsequently, using small molecule library screening and in situ ChIA-PET , we discovered that bromodomain protein 9 (BRD9) plays an important role in maintaining cell stemness by regulating enhancer-promoter interactions . In addition, we have developed a new 3D genome visualization and analysis tool, EXPRESSO, which integrates the most comprehensive 3D genomics and epigenetics data available for download and viewing to date.