RESEARCH

Epigenetic regulation, including the chemical modifications on DNA and the DNA-packaging histone proteins, controls where, when, and what genes are expressed in eukaryotic cells. Epigenetics is the major mechanism conferring diverse cell types of our body that come from the same DNA sequence. It has been shown that epigenetic regulation has profound impacts on human development and disease. Cancer cells, not only carry frequent mutations in epigenetic-modulating genes, but also reply on distinct epigenetic mechanisms for cancer initiation, maintenance, and drug resistance. Understanding the roles of epigenetic modifications, as well as their alterations in the pathogenesis of human cancers, is critical for developing novel therapeutic strategies for cancer treatment.

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Epigenetic information provides an additional layer of control for gene expression.

The research in our lab aims to improve our understanding of epigenetic mechanisms in the development of human cancers. We choose acute myeloid leukemia (AML) as our major cancer model, because AML has fewer mutations than most other cancers and many of the mutations in AML hit genes encoding epigenetic regulators. Our research aims to understand epigenetic regulation in human cancers, determine critical oncogenic pathways, and use the knowledge to develop targeted therapeutic approaches. We are taking multifaceted approaches involving stem cell biology, cancer biology, chromatin biology, as well as genomics and computational biology. The specific research directions of our lab are list below.

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We use AML as a model to study cancer epigenetics because of its unique characteristics.

Understanding the molecular basis of driver mutations

At least 70% of AML patients carry mutations of epigenetic-modulating genes, however, we are still at the very early stage in understanding these epigenetic modulators and their mutations in AML. It is important to understand the molecular mechanisms that how these mutations contribute to oncogenic transformation, before we develop therapeutic approaches to reverse the oncogenic changes to the cells. As an example, our previous work has systemically delineated the aberrant epigenome caused by DNMT3A mutation in a murine AML model, and identified DOT1L as a target for treating DNMT3A-mutated leukemia (Cancer Cell, 2016). We have a great interest in understanding AML-related mutations in epigenetic-modulating genes, and we will use state-of-the-art approaches to study the mutants at biochemical, genomic, cellular, and whole-animal levels.

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We use next-generation sequencing technology to profile epigenetic modifications at genome-wide levels.

Discovery of novel targets for cancer epigenetic therapies

A growing body of evidence suggests that cancer cells usually acquire aberrant epigenetic programs to activate oncogenes or silence tumor suppressor genes to establish and sustain the malignant state. Unlike genetic alterations, the changes of epigenetic modifications are reversible, allowing us to restore the normal epigenetic states of affected genes, and ultimately, to reprogram cancer cells toward a normal or non-malignant status. Recently, a number of small molecules targeting responsible epigenetic modulators have developed and are in the clinical trials for treating a variety of human cancers, including acute myeloid leukemia (see this review). However, our knowledge on the epigenetic and transcriptional dependency of leukemia remains limited. We are using candidate approach, genome-wide screening, in vitro and in vivo models to identify and systemically characterize novel targets for epigenetic therapies in human leukemia.

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We identify novel targets responsible for cancer-specific transcriptional and epigenetic regulations.

Development of novel epigenome editing tools

The localization of epigenetic medications and modulators can be profiled in a genome-wide scale using next-generation sequencing technologies, however, the functional readout of an epigenetic state at a specific loci remains poorly understood. From a clinical point of view, epigenetic therapy uses agents to inhibit the overall activity of an epigenetic modulator, which will lead to a global change of the epigenetic state and inadvertently affect other genomic regions, leading to profound secondary effects. To dissect the functional roles of an epigenetic medication or a modulator, we use CRISPR/dCas9 technology to develop new tools for targeted epigenome manipulation at a specific genomic locus. This research direction will help us better understand how an epigenetic modulator works, and offer new opportunities for translation into clinical applications for cancer therapy.