Motivation

While every cell within the body shares identical genetic information, the epigenome (various biochemical modifications on DNA or histones) is dynamically modulated by diverse environmental signals to regulate gene expression in different cell types and during development. Trillions of bacteria live inside the gastrointestinal tract are collectively referred to as the gut microbiota. The gut microbiota is necessary to maintain host health by digesting complex carbohydrates, providing non-nutrient essential factors, and preventing pathogenic microbes from colonizing. Many bacteria-derived metabolites have been shown to alter the metabolic and inflammatory pathways in the host. Over the last few decades, lifestyle changes (sanitation, antibiotics usage, the consumption of high-fat and high-fructose diets, etc.) have been speculated to contribute to the onset of several immune, neurological, and metabolism-related diseases. More recently, imbalances in the gut microbiota are associated with type 1 and 2 diabetes, obesity, amyotrophic lateral sclerosis, Parkinson’s disease, atherosclerosis, and other ailments. Although correlations have been observed between the development of different chronic diseases and dysbiosis of the gut microbiome, the molecular mechanism underlying microbiota-mediated alternations in gene regulation is still largely uncharacterized. This research group aims to understand how the environmental conditions modulate host epigenome through gut microbiota and discover novel therapeutic targets for human diseases.

Research Interests

Developing new toolkits for microbiome remodeling

Genome-wide sequencing studies have revealed that the composition of gut microbiota is altered in atherosclerosis and many other human diseases, indicating that the gut microbiota is a key extrinsic factor in regulating gene expression in the host. Due to the inability to specifically modulate different bacterial species within gut microbiota, the functions of different groups of species within gut microbiota and how they interact with the host is still not clear. To better understand and characterize the roles of different species in promoting atherosclerosis, we develop the in vitro platform to identify chemical modulators for gut microbiome and the in vivo atherosclerosis model to evaluate the effects of gut microbiome in the host. We show that selective remodeling in gut microbiome inhibits the development of atherosclerosis and identify several molecular pathways that are mediated by microbiome in the host. We are actively developing new tools for improving microbiome remodeling, as well as rewiring gene regulatory programe within gut microbiota.

Characterizatin of functional cis-regulatory elements

Enhancers have been recognized as integrated transcription factor (TF) binding hubs to fine tune gene expression under different stimuli and between different cell types. The chromatin state and spatial interactions between regulatory elements and target genes are crucial for cell-type-specific gene expression during normal development and disease progression. Recently, we develop and utilize highly multiplexed CRISPR-based perturbation and sequencing to identify hundreds of pro-growth enhancers across major cancer types. We seek to expand the usage of this unbaised functional perturbation assay to uncover functional enhancers crucial for different physiological phenotypes.