1) Mechanisms underlying the tissue specificity of cancer-associated chromatin abnormality
In contrast to tissue- and sequence-specific transcription factors, chromatin regulators are ubiquitously expressed and often target hundreds of genes. Paradoxically, cancer-associated mutations in chromatin regulators exhibit a high degree of tissue specificity. We are interested to address why/how does the broad activity of chromatin regulator produce pathway-specific effect. To this end, we are using novel epigenome-editing tools to discern the 'driver' vs. 'passenger' downstream targets following global chromatin perturbation.
2) Response and resistance mechanisms to chromatin-targeted drugs
Chromatin regulators have emerged as popular drug targets in oncology and other human diseases and a number of epigenetic drugs are FDA-approved or in clinical development to treat cancer. However, little is known about the potential mechanisms and biomarkers that predict the response or resistance to these drugs. We plan to employ Crispr/Cas9-mediated genomic screening approaches to systematically study the mechanism of action underlying cancer epigenetic drugs.
3) Novel tools to study chromatin functionality and dynamics
While traditional epigenomic profiling methods (eg. ChIP-seq) have greatly facilitated our understanding of chromatin organization, they provide largely correlative evidence and lack the ability to reveal functionality and dynamics of chromatin modifications. We are interested in developing new tools that allow us to study chromatin in high-resolution and in real-time.