The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation

Abstract

Yes-associated protein (YAP) is a potent transcription coactivator acting via binding to the TEAD transcription factor, and plays a critical role in organ size regulation. YAP is phosphorylated and inhibited by the Lats kinase, a key component of the Hippo tumor suppressor pathway. Elevated YAP protein levels and gene amplification have been implicated in human cancer. In this study, we report that YAP is inactivated during embryonic stem (ES) cell differentiation, as indicated by decreased protein levels and increased phosphorylation. Consistently, YAP is elevated during induced pluripotent stem (iPS) cell reprogramming. YAP knockdown leads to a loss of ES cell pluripotency, while ectopic expression of YAP prevents ES cell differentiation in vitro and maintains stem cell phenotypes even under differentiation conditions. Moreover, YAP binds directly to promoters of a large number of genes known to be important for stem cells and stimulates their expression. Our observations establish a critical role of YAP in maintaining stem cell pluripotency.[Keywords: YAP; Hippo; stem cells; TEAD] Supplemental material is available at http://www.genesdev.org.

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…The elevated reprogramming efficiency depends on TAZ because concomitant knockdown of TAZ blocked the effect of Lats2 knockdown. In an independent report, co-expression of YAP was also shown to improve the efficiency of human iPSC generation by OSK (Lian et al, 2010), although in a separate study, YAP did not show any significant effect when all four factors OSKM were used (Chia et al, 2010). Nevertheless, it is still clear that inhibition of the Hippo pathway would improve iPS generation although the role of TAZ and YAP in different species might be different.…”

“…However, only until recently, it was demonstrated that YAP as well as its transcription factor partner TEAD promotes ES cell self-renewal. When mouse ESCs were induced to differentiate, YAP was inactivated as indicated by decreased protein level and increased phosphorylation (Lian et al, 2010;Tamm et al, 2011). However, YAP overexpression prevents mouse ESCs from differentiation even under differentiation condition such as leukemia inhibitory factor (LIF) withdrawal (Lian et al, 2010;Tamm et al, 2011).…”

“…When mouse ESCs were induced to differentiate, YAP was inactivated as indicated by decreased protein level and increased phosphorylation (Lian et al, 2010;Tamm et al, 2011). However, YAP overexpression prevents mouse ESCs from differentiation even under differentiation condition such as leukemia inhibitory factor (LIF) withdrawal (Lian et al, 2010;Tamm et al, 2011). In addition, YAP knockdown leads to loss of pluripotency under a condition that would normally support stemness (Lian et al, 2010;Tamm et al, 2011).…”

“…However, YAP overexpression prevents mouse ESCs from differentiation even under differentiation condition such as leukemia inhibitory factor (LIF) withdrawal (Lian et al, 2010;Tamm et al, 2011). In addition, YAP knockdown leads to loss of pluripotency under a condition that would normally support stemness (Lian et al, 2010;Tamm et al, 2011). Chromatin immunoprecipitation (ChIP) experiments demonstrated that YAP-TEAD bind to promoters of many stemnesspromoting genes such as Oct4 (Lian et al, 2010;Tamm et al, 2011).…”

“…In addition, YAP knockdown leads to loss of pluripotency under a condition that would normally support stemness (Lian et al, 2010;Tamm et al, 2011). Chromatin immunoprecipitation (ChIP) experiments demonstrated that YAP-TEAD bind to promoters of many stemnesspromoting genes such as Oct4 (Lian et al, 2010;Tamm et al, 2011). Intriguingly, knockdown of TAZ in human ESCs also led to differentiation and loss of pluripotency, although YAP was intact (Varelas et al, 2008).…”