Research in Yi Zhang's laboratory is focused on epigenetic modifications, particularly DNA methylation and covalent histone modifications, which play an important role in regulating chromatin dynamics, and therefore have a significant impact on gene expression. They have investigated how epigenetic modification-mediated dynamic changes in chromatin structure affect gene expression, cell lineage commitment, stem cell pluripotency, and stem cell self-renewal. In addition, they have studied mis-regulation of epigenetic factors and how that contributes to the development of diabetes, neurological diseases, and cancer.

The Zhang lab also investigates the epigenetic mechanisms in embryonic development, stem cell reprogramming, β-cell regeneration, and drug addiction. Yi Zhang's long-term goal is to apply what his group has learned in basic research to studies of human diseases.