How do cells retain their identity?
The human body has ~37 trillion cells and over 200 different cell types. We are interested in uncovering the molecular mechanisms that establish and maintain cellular identity during embryonic development and cellular differentiation. One elegant yet complex strategy utilized by the cells is to turn ON (active gene expression) or OFF (gene silencing) a select subset of genes. How does the cell know which subset of genes needs to be OFF? And how does the cell know to keep these in the OFF state to maintain cellular identity?
Our lab approaches these questions by utilizing a multi-disciplinary approach combining structural biology techniques such as single-particle cryo-electron microscopy (cryo-EM), cryo-electron tomography (cryo-ET) with chemical biology and biochemistry. We study chromatin modifier enzymes, which play critical roles in marking genes for either gene expression (ON) or gene silencing (OFF). We are particularly interested in gene-silencing enzymes such as Polycomb Repressive Complexes, DNA methyltransferase, and Histone deacetylases (HDACs), which play broad roles in cellular identity and genome integrity.
Our lab is at the forefront of utilizing new cryo-EM and cryo-ET methodologies to study these enzymatic processes in vitro and in situ. We are interested in understanding how RNA and nucleosomes regulate the activity of these enzymes, as well as developing new strategies to target these enzymes in diseases. Defects in these enzymes are found in almost all cancers and are fundamental to the disease pathology of many disorders, including neurodegenerative diseases.
Our research vision is to provide a molecular-level understanding of gene silencing. The outcomes from our research have broad implications in developing new avenues targeting diseases and understanding how these enzymes contribute to genome surveillance in the fight against foreign DNA invasion such as those from viruses.
