The three billion base pairs of the human genome, if stretched out linearly, would exceed 2 meters in length. Remarkably, this amount of DNA is packaged inside of a nucleus that is 5-10 micrometers wide in diameter. The compaction of the genome in the nucleus is non-random. Recent evidence has indicated that a critical feature of genome organization is that regions of the genome form self-associated domain structures on a megabase scale. These structures are generally known as topologically associated domains (TADs) and have been demonstrated to play a critical role in facilitating proper gene regulation. Our recent studies revealed that the integration of the TAD organization with cancer genomic datasets provides unique insights into the mechanisms and functional consequences of somatic alterations observed in human tumors.
In our lab, we focus on the development and application of algorithms that analyze and interpret multi-omics data from individual patients for prospective clinical uses. Broadly, we strive to gain a better understanding of mutations (somatic and germline) in cancer cells which will enable new translational inventions and accelerate development of clinical interventions.
Elucidating the functional consequences of complex genomic alterations
Cancer genomes are predominantly restructured due to somatically-acquired, catastrophic rearrangements. However, our ability to determine the clinical implications of these complex rearrangements in cancer genomes remains limited. We develop novel computational methods to utilize chromatin organization information for analyzing the rearranged chromosomes, and elicit information about the altered gene regulatory landscapes that result from these complex rearrangements. We apply these methods to investigate the potential clinical implications of altered chromosomes in human brain tumors, cancer types which exhibit the highest number of complex genomic rearrangements among human malignancies.
Investigating the influence of epigenome on mutational processes
Somatic mutations arise during the life of a cell and in the generation of its progeny. Accumulation of mutations can lead to age-related diseases, and those occurring in cancer driver genes may ultimately lead to tumorigenesis and the development of clinically detectable disease. However, the spatio-temporal processes that direct mutation rates throughout cancer evolution are not fully understood. The hierarchical folding of genomic DNA within the nucleus is intimately linked with transcriptional regulation and DNA replication. We investigate the effects of three-dimensional genome organization on the distribution of somatic mutations in human cancers with the aim of elucidating the potential role of genome folding on DNA damage and repair processes.
Developing computational methods for integrative analysis of large genomic datasets
Our lab is involved multiple genomic characterization efforts involving generation of multi-omics datasets from patients with different tumor types or exhibiting a spectrum of clinical responses. Therefore, a key research area in the lab is to develop computational tools to mine and visualize diverse genomic assay outputs in order to expand our understanding of how different molecular processes are involved in tumor initiation, progression and response to cancer therapies.