Genetic approaches to understanding the tumor epigenome
We are interested in understanding basic mechanisms governing chromatin organization and access during normal and cancer development. Eukaryotic cells develop sophisticated mechanisms to package and access their genetic information. Recent studies uncover that proteins involved in genome regulation are frequently altered in human developmental syndromes and cancers. These findings agree with laboratory observations that cancer cells often display abnormal nuclear architecture, and raise the questions of whether and how aberrant chromatin landscape facilitates disease development.
Our previous work have largely focused on hotspot, gain-of-function mutations in chromatin modulators and regulators, including IDH1/2 and histone H3, that are frequently identified in a number of adult and pediatric cancer types. Collectively we have delineated the biochemical mechanisms by which these mutations alter global chromatin landscape. We also demonstrated that chromatin mutations are pro-oncogenic through the blockade of cellular differentiation. While these findings provide compelling evidence for a causal role of chromatin dysregulation in oncogenesis, how genetic mutations in chromatin enzymes interact with non-genetic mechanisms (eg. chromatin cross-talk; micro-environment) to shape tumor’s epigenome landscape remains poorly understood. We aim to employ both hypothesis-driven as well as systems approaches to dissect the complex chromatin regulatory network that is reprogrammed to endow cancer cells with tumor-promoting potentials.
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.