Research Overview

The research interests in our laboratory lie in the intersection of cancer biology and epigenetics. We focus on chromatin - the complex of DNA and histone proteins - and its regulatory network. Chromatin is the physiological template of the eukaryotic genome through which transcription factors, signaling pathways, and other internal and external cues alter gene activity and cellular phenotypes. Cancer genome studies revealed that at least 50% of human cancers harbor mutations in genes encoding chromatin-associated factors, suggesting widespread roles of chromatin misregulation in cancer. We strive to understand chromatin function and its dysregulation in human cancer, with a focus on addressing how chromatin-based mechanisms regulate cellular fate transition and plasticity that endow cancer cells with tumor-promoting potentials. We use a host of different approaches in genetics and epigenetics, biochemistry, genome-wide sequencing, bioinformatics and functional genomics to address these questions. We are also interested in leveraging our basic mechanistic discoveries for therapeutics development. We have multiple areas of ongoing research in the lab:

Decoding the Epigenome

Our genome is decorated with diverse chemical modifications on histone proteins that package the DNA. These modifications constitute an essential layer of information (referred to as epigenome) to regulate genome architecture and function. How this information is interpreted to impact a cell’s fate and behavior, and how this process goes awry in human diseases remain poorly understood. Ongoing projects focus on chromatin readers, proteins that dock on specific histone modifications. We seek to understand how reader-mediated process translates epigenetic information to downstream events that ultimately determine the cell fate.

Drugging the Epigenome

Epigenetic dysregulation is a common feature of many cancers. The field of cancer epigenetics has witnessed exciting translation of basic mechanistic understanding to the development of epigenetic modulatory drugs as novel cancer therapies. However, for many epigenetic agents, their mechanisms of action (e.g. what determines the response and resistance to these agents) remain poorly understood. Our group is actively engaged in the development and/or characterization of drugs that target newly identified epigenetic mechanisms, with the goal of advancing our basic understanding of epigenetic regulation, and at the same time facilitating clinical application of epigenetic therapies.

Epigenomic Reprograming and Cell Plasticity

Cancer cells are difficult to eliminate as they are highly adaptive and resilient. Epigenomic reprogramming is emerging as a potential mechanism underlying adaptive cell fate transitions. This is particularly relevant under stress conditions such as during cancer metastasis, the deadliest step of cancer progression that involves constant adaptation of metastatic cells to the changing microenvironment. How cancer cells acquire the ability to metastasize remains elusive. While metastatic cells exhibit stable transcriptional programs that are functionally linked to metastatic progression, genomic analyses thus far have failed to identify consistent genetic mutations responsible for the emergence of such pro-metastatic gene programs. We propose that a subset of cancer cells acquire an altered chromatin state in response to the stressful microenvironment, which allows them to acquire cellular plasticity to adapt and thrive. Investigation of this hypothesis will bring conceptual advances into our understanding of the origin of metastatic traits, and have the potential to illuminate new therapeutic strategies.