The long-term goal of my research program is to elucidate the key epigenetic mechanisms of establishing and maintaining pluripotency during reprogramming and development, employing both the oocyte (nuclear transfer) and cellular reprogramming systems (transcription factors and small molecules), in the hope of translating our research findings into therapeutic applications.
Reprogramming somatic cells to become pluripotent stem cells holds great promise for stem-cell-based therapeutics. One major barrier to progress in this area lies in our present inability to identify which stem cells are truly pluripotent. Induced pluripotent stem cells (iPSCs), which are reprogrammed by transcription factors, are remarkably similar in many key respects to embryonic stem cells (ESCs). However, studies have demonstrated that iPSCs have greater inherent variability and lower efficiency for differentiation than do ESCs. This suggests that each iPSC line may be unique in its potential to differentiate. These inherent differences among iPSC lines complicate research and may influence their clinical behavior as well. Therefore, iPSC pluripotency assessment and quality control are the first critical step for stem cell-based therapeutics. In animals, a typical test for pluripotency is to make chimeras with developing embryos. However, for ethical reasons, such a test cannot be used in the human system. Understanding how stem cells acquire pluripotency and plasticity to differentiate, and developing effective methods to assess the stem cell potentials are important both for research and for clinical applications. We and others have shown that iPSCs from mice can have markedly different potential to generate “all-iPS” animals, even when the cells have similar transcription profiles. This difference suggests an essential role for epigenetic mechanisms in regulating stem cell pluripotency. In pluripotent stem cells, developmental bivalent (DB) genes are transcriptionally inactive but ready to activate upon differentiation. This state of “poise,” in which the gene remains ready for later activation, is marked by both H3K4me3 and H3K27me3 modifications at the promoter. DB genes are thought to be critical to maintaining lineage commitment programs, which are pre-programmed to activate in stem cells. Our studies suggest that a crucial part of this “program” in the DB genes is the promoter chromatin remodeling mediated by histone variants during reprogramming.
Although it has been over 50 years since the first experiment by John Gurdon demonstrated that the egg or oocyte could reset a differentiated nucleus into pluripotency, still now the oocyte is mechanistically considered to be a “black box” - we know that it can reset a somatic nucleus, but we do not know how and what maternal factors are involved in this process. My laboratory is dedicated to understanding the role of maternal factors that drive the reprogramming of highly specialized germ cells and somatic nucleus towards a totipotent embryo.
Current research projects in my laboratory include (1) defining the contribution of histone variant H3.3 for pluripotency during reprogramming and differentiation using iPSCs as the model, (2) investigating the role and function of histone H3.3 during fertilization and embryogenesis using our unique mouse models, and (3) mechanisms of oocyte reprogramming.