The human genome has around 3,000,000,000 bases, and encodes around 2,500 chromatin-associated proteins that directly or indirectly bind the DNA sequences. One of the major goals of our lab is to understand the principles and mechanisms of genome regulation. The mammalian genome is spatially organized in the nucleus to facilitate cell type-specific gene expression. Investigating how chromatin determines this specificity remains a big challenge due to the high-scale complexity of the genome: various kinds of chromatin regulators, different types of functional DNA elements, and sophisticated interactions between the two. 

To solve these challenges, we are developing high-throughput technologies – both experimental approaches and AI/computational tools – to discover functional DNA elements and novel genome regulators. Coupling with genomic, molecular, and chemical biology approaches, we aim to understand the fundamental principles and molecular mechanisms of genome regulation from single-base resolution to chromosome-level scales. We further investigate how genome regulation goes awry in diseases, and how we can manipulate, restore, and de novo synthesize the regulatory circuits in the genome to develop new therapeutics. 

Some immediate questions/projects that we are working on: 

• How do chromatin-associated proteins orchestrate global genome regulation?

• How to study the dynamic regulation of chromatin-associated proteins, particularly during cell fate transitions?

• What factors determine TAD boundaries in the mammalian genome? 

• How to categorize chromatin interaction types, and what factors define them?

• What is the fundamental mechanism for determining chromatin organization in mammalian genomes and in species where CTCF is absent or not conserved?

• How does 3D genome organization regulate gene transcription?

• How to design and synthesize new chromatin domain structures? Can we evolve new principles of genome organization beyond nature?