Understanding the fundamental mechanisms of 3D genome organization

A major focus of the lab is to understand how chromosomes fold in the interphase nucleus and how this affects diverse processes in the nucleus, including gene regulation, DNA replication, and DNA repair. We use Chromosome Conformation Capture-based method to study higher order chromatin structure to understand the fundamental features of how our genomes are organized across cells and across the tree of life. In previous work, we had found that chromosomes are folded into Topologically Associating Domains (TADs). Functionally, TADs restrict enhancer-promoter interactions in the genome, suggesting that they serve a role in functional specification of gene regulation. We have recently focused on using protein-degron tagging based methods to better understand the mechanisms of TAD formation and how TADs contribute to patterns of gene expression across cell types. We are particularly interested in understanding how TADs contribute to cell-type specific patterns of gene expression, and how this contributes to cell fate and specification.

Alterations to 3D genome organization in cancer

Cancer cells are subject to genomic instability and can harbor high rates of genetic alterations that alter how our genomes encode information. Our lab is interested in how genetic mutations in cancer genomes alter the 3D folding and gene regulatory landscape of cancer cells, and how this contributes to oncogenesis. In particular, we have focused on how structural variants, including inversions, deletions, duplications, and translocations, which fragment and restructure our genomes, lead to changes in 3D genome folding and altered oncogene expression. We have focused on characterizing naturally occurring patterns of structural variation in cancer genomes and using CRISPR/Cas9 engineering to generate de novo structural variants to understand their consequences. Our long-term goal is to use our knowledge of the alterations to 3D genome organization in cancer to further personalized medicine and design better therapies for cancer patients.

Novel technology development

To study 3D genome architecture and its role in human health and disease, we also focus on the development of novel technologies. This has included novel computational tools, including methods to perform haplotype phasing or identifying structural variants using Hi-C data. In recent years, we have also focused on the development of novel single-cell methodologies to profile 3D genome organization. We have co-developed the single-nucleus methyl-3C sequencing (snm3C-seq) method to jointly analyze DNA methylation and 3D genome folding simultaneously in single cells. We have applied these tools to characterize genome organization across a variety of cell types and tissues. In ongoing work, we are further developing these technologies and exploring novel ways of using these single cell methods to better understand 3D chromatin organization in diverse contexts.