Mary Donohoe                          
Assistant Professor                  

                                

Regenerative medicine holds enormous promise for patients with degenerative and other diseases. But the foundations for safe and effective treatment depend on a deep understanding of the mechanisms of lineage specification, cellular reprogramming and the optimal environment for maintaining the phenotypic stability of pluripotent stem cells, and the specific lineages that can be directed to differentiate from them. These foundations will, in large part, be defined through experimental investigation of factors affecting pluripotency, specification and commitment of these lineages in normal embryogenesis in animal models. Knowledge gained will translate into a deeper understanding of the abnormalities associated with human birth defects.

The Donohoe lab investigates the gene regulation and epigenetics in early development.  Our long-term goal is to understand a fundamental developmental event by investigating the mechanisms directing its establishment and differentiation of the pluripotent cell population resident in mammalian embryos. Our ongoing and proposed experiments address not only how local interactions between a cell and its immediate neighbors give rise to an emergent, higher-level of organization, but also how this process is regulated mechanistically by specific genes or gene networks.  Our intent is to unravel an early regulatory control circuit for the commitment of cell fate from pluripotency.

Pluripotency of embryonic stem (ES) cells is controlled by defined transcription factors.  During differentiation, mouse ES cells undergo genome-wide epigenetic reprogramming, a process exemplified by changes that take place during X-chromosome inactivation (XCI).  XCI is a crucial epigenetic developmental event that silences one female X-chromosome to achieve gene dosage differences between male (XY) and females (XX).  XCI and cell differentiation are tightly couples, as blocking one process compromises the other.  We have discovered that the pluripotency factor, Oct4, crucial to maintain “stemness” cells, is linked to XCI.  Our future experiments will further define the role for other trans-factors involved in both pluripotency and XCI.  Our goal is to unravel an early regulatory control circuit for the commitment of cell fate from pluripotency.