Elucidating the structures and dynamics of complex genomes.
Our primary interest is to elucidate the structures and dynamics of all functional DNA elements in complex genomes through DNA sequencing analysis of genetic variations in genomes and transcriptomes. To facilitate such understanding, we contributed to the technology development for ENCODE. We developed high-throughput DNA sequencing and mapping methodologies, including the paired-end-tag (PET) sequencing strategy for RNA-PET/Seq, ChIP-PET/Seq, DNA-PET and ChIA-PET analysis. We are applying these sequencing-based methodologies to address complex genetic questions between normal versus disease states. A specific interest is to apply ChIA-PET and related methodologies to understand the three-dimensional (3-D) higher-order structures of chromosomal folding conformation and their impact on nuclear processes, such as gene transcription regulation and DNA replication.
We have demonstrated that genomic elements such as promoters and enhancers are extensively intertwined with one another genome-wide to form functional transcriptional foci in the nuclei for specific and coordinated transcription regulation. More importantly, we demonstrated genetic variations in regulatory elements involved in chromatin-folding architectures could alter higher-order chromatin interaction architecture and impact gene transcription controls, and thus potentially cause diseases. We are also applying the integrated genomics approach to study internal and external signals and protein factors that orchestrate the 3-D changes of chromatin-interaction architectures and alter the outcomes of gene expression. Furthermore, the induction time courses could provide a system to study the dynamic changes of chromatin structure and transcription regulation in the fourth-dimensional (4-D) space.
Overall, our studies have provided a new dimension of combinatorial controls of gene transcription within the context of chromatin looping architecture in eukaryotic genomes. The work has paved the way toward presenting 3-D topographic maps of human genomes for better understanding of their functions in health and disease.
Our pioneering efforts in technology development have necessitated that we also concomitantly develop new computational tools to process and analyze the unique types of genomic data that our technology has generated. My recent interests in computational analysis are to integrate multi-level genomic data in order to construct multi-dimensional regulatory networks to ultimately elucidate the complex processes that regulate gene transcription using a systems approach.