Howard Hughes Medical Institute Investigator
The human embryonic stem cell is defined not only by its origin but also by its function: it must retain the capacity for perpetual self-renewal and pluripotency. Unfortunately, a diminished efficiency in either of these processes can threaten the identity of the stem cell, leading to spontaneous differentiation, a failure to undergo induced differentiation, or apoptosis. We have hypothesized that human embryonic stem cells (hESCs) contain an increased capacity to protect their proteomes from fluctuations in the cellular environment that would otherwise lead to a loss of stem cell identity. As such, we predicted that the stem cell would exhibit a heightened capacity for ensuring the effective synthesis, chaperoning, and degradation of its proteins in comparison to its differentiated counterparts.
Supporting our hypothesis, we recently discovered that hESCs exhibit robust levels of proteasomal activity in comparison to differentiated cells. Our data suggest that at any given time point, a greater backlog of non-functioning proteins awaits degradation in differentiated cells than in stem cells. The transcription factor FOXO4, a critical regulator of stress resistance and longevity in differentiated cells, modulates the increase in hESC proteasomal activity. FOXO4 is also a well-characterized upstream regulator of multiple stress responsive genes, the role for which in hESCs is yet unknown. It also has a pronounced and seemingly independent effect on hESC pluripotency, specifically with regards to neuronal differentiation. Thus, the upstream role of FOXO4 may diverge to affect multiple facets of hESC function, including its general proteostasis and capacity for neurogenesis.