Abstract
Sirt2, a member of the NAD+-dependent protein deacetylase family, is increasingly recognized as a critical regulator of the cell cycle, cellular necrosis and cytoskeleton organization. However, its role in embryonic stem cells (ESCs) remains unclear. Here we demonstrate that Sirt2 is up-regulated during RA (retinoic acid)-induced and embryoid body (EB) differentiation of mouse ESCs. Using lentivirus-mediated shRNA methods, we found that knockdown of Sirt2 compromises the differentiation of mouse ESCs into ectoderm while promoting mesoderm and endoderm differentiation. Knockdown of Sirt2 expression also leads to the activation of GSK3β through decreased phosphorylation of the serine at position 9 (Ser9) but not tyrosine at position 216 (Tyr216). Moreover, the constitutive activation of GSK3β during EB differentiation mimics the effect of Sirt2 knockdown, while down-regulation of GSK3β rescues the effect of Sirt2 knockdown on differentiation. In contrast to the effect on lineage differentiation, Sirt2 knockdown and GSK3β up-regulation do not change the self-renewal state of mouse ESCs. Overall, our report reveals a new function for Sirt2 in regulating the proper lineage commitment of mouse ESCs.
Highlights
Embryonic stem cells (ESCs) are pluripotent and self-renewing cells that are derived from the inner cell mass of an embryo [1]
Real-time PCR analysis showed that Sirt2 expression was up-regulated in both RA-mediated and embryoid body (EB) differentiation of mouse ESCs, indicating that Sirt2 may have a role in mouse ESC differentiation
We examined the effect of knocking down Sirt2 expression in mouse ESCs
Summary
Embryonic stem cells (ESCs) are pluripotent and self-renewing cells that are derived from the inner cell mass of an embryo [1]. ESCs have the ability to generate all three germ layers: ectoderm, mesoderm, and endoderm. If cultured in specific conditions, ESCs can differentiate into multiple cell lineages [2]. These unique properties make them especially valuable for regenerative medicine and cell replacement therapies. In vitro induction of ESC differentiation into a particular cell lineage often results in only a small proportion of properly differentiated cells [3]. Understanding the mechanism of lineage commitment is necessary for the development of practical applications for ESCs
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