Nuclear factor, erythroid 2‐like 2 (Nrf2) is a master transcription factor for
cellular defense against endogenous and exogenous stresses by regulating
expression of many antioxidant and detoxification genes. Here, we show
that Nrf2 acts as a key pluripotency gene and a regulator of proteasome
activity in human embryonic stem cells (hESCs). Nrf2 expression is highly
enriched in hESCs and dramatically decreases upon differentiation. Nrf2
inhibition impairs both the self‐renewal ability of hESCs and reestablish‐
ment of pluripotency during cellular reprogramming. Nrf2 activation can
delay differentiation. During early hESC differentiation, Nrf2 closely co‐
localizes with OCT4 and NANOG. As an underlying mechanism, our data
show that Nrf2 regulates proteasome activity in hESCs partially through
proteasome maturation protein (POMP), a proteasome chaperone, which
in turn controls the proliferation of self‐renewing hESCs, three germ layer
differentiation and cellular reprogramming. Even modest proteasome inhi‐
bition skews the balance of early differentiation toward mesendoderm at
the expense of an ectodermal fate by decreasing the protein level of cyclin
D1 and delaying the degradation of OCT4 and NANOG proteins. Taken to‐
gether, our findings suggest a new potential link between environmental
stress and stemness with Nrf2 and the proteasom