We are primarily focused on the following:
How various dynamic epigenetic changes in chromatin structure impact gene expression during stem cell pluripotency/self-renewal, cellular differentiation, and reprogramming.
How three-dimensional chromosomal structure and dysregulation contribute to development of diseases such as aging and cancer.
The long-term goal of The Wang Lab is to translate our understanding of these complex mechanisms to studies of human diseases.
Stem Cell Pluripotency and Self-Renewal
Significant phenotypic differences exist between queens and worker honey bees, yet both develop from identical larvae. What drives their developmental differences is the amount of Royal Jelly fed to the larvae: all larvae receive these nutrients, however, the selected larvae to become queens are fed far larger quantities. The active component of Royal Jelly, called Royalactin, has regenerative effects in mammals and can impact longevity and fertility across different species. In studying the effects and biology of Royalactin, we discovered its mammalian structural analog, Regina.
Studies on the current method of culturing mouse embryonic stem cells have shown the deleterious effects of long-term cultured ES cells in a group of inhibitors that target MAPK/ERK Kinase (Mek) and glycogen synthase kinase-3 (GSK3), in conjunction with Leukemia inhibitory factor (LIF). Prolonged suppression of these pathways limit the cells’ developmental potential, rendering them ineffective for long-term applications. Using Royalactin and Regina, we have successfully maintained long-term stem cell pluripotency without compromising genetic integrity and renewed the ES cells to an earlier embryonic state. We are actively working on completing our understanding of the biology of these proteins and other applications for their use.
Dynamic Chromosomal Architecture
The distinct shape in which our genome is organized can determine and play a significant role in gene expression. How chromatin folds on itself naturally and abnormally is particularly important in the contexts of cancer and development. We created CLOuD9, a unique tool that allows for selective and reversible modification of chromatin loops. Using this tool, we can create artificial loops, reverse de novo loops, and study their effects on gene expression.