Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation

Abstract

Approximately, 30% of embryonic stem cells (ESCs) die after exiting self-renewal, but regulators of this process are not well known. Yap1 is a Hippo pathway transcriptional effector that plays numerous roles in development and cancer. However, its functions in ESC differentiation remain poorly characterized. We first reveal that ESCs lacking Yap1 experience massive cell death upon the exit from self-renewal. We subsequently show that Yap1 contextually protects differentiating, but not self-renewing, ESC from hyperactivation of the apoptotic cascade. Mechanistically, Yap1 strongly activates anti-apoptotic genes via cis-regulatory elements while mildly suppressing pro-apoptotic genes, which moderates the level of mitochondrial priming that occurs during differentiation. Individually modulating the expression of single apoptosis-related genes targeted by Yap1 is sufficient to augment or hinder survival during differentiation. Our demonstration of the context-dependent pro-survival functions of Yap1 during ESC differentiation contributes to our understanding of the balance between survival and death during cell fate changes.

YAP and TAZ protect against white adipocyte cell death during obesity

“…When analyzing transcriptomic changes in white adipocytes of Ad-Yap/Taz-KO mice fed HFD for 4 weeks compared to wildtype littermates, we observed that the anti-apoptotic genes Bcl2 and Bcl2l2 were downregulated, and that the pro-apoptotic gene Bim was strongly upregulated in the absence of YAP/TAZ. This is consistent with previous data, which showed that, during embryonic stem cell (ESC) differentiation, YAP attenuates apoptosis primarily through transcriptional upregulation of antiapoptotic factors, including BCL2, BCL2L1, and MCL-1 69 , as well as with observations, which showed that YAP/TAZ promote cell survival through suppression of the pro-apoptotic protein BIM, whereas YAP/TAZ knockdown increased BIM expression 70 . Similarly, it has been shown that overexpression of YAP or TAZ suppresses BIM expression 71,72 .…”

Effects of Spaceflight and Simulated Microgravity on YAP1 Expression in Cardiovascular Progenitors: Implications for Cell-Based Repair

“…Thus, the possibility of conditioning adult CPCs with short term exposure to microgravity to overexpress transcripts, including YAP1, which promote the survival of cardiac stem cells capable of repair could unexpectedly be beneficial. This novel path may be worth pursuing as a potential pretreatment and therapy for myocardial infarction patients on Earth, as high levels of YAP1 protect cells during differentiation and aid in improving cardiac function [27,28,29]. The following study is focused on the impact of microgravity experienced in spaceflight and simulated microgravity on the Hippo-YAP signaling pathway in cardiovascular progenitor cells.…”

Tumor Suppressor LKB1 inhibits both the mRNA Expression and the Amplification of hTERC by the Phosphorylation of YAP in Lung Cancer Cells

“…YAP is a key effector molecule downstream of Hippo signaling pathway 8. It regulates signal transduction inside and outside the nucleus through phosphorylation, and acts as a transcription co-activator to regulate the activity of transcription factors 8,9,10.…”

“…Hippo signaling pathway, firstly discovered in Drosophila melanogaster 8, is a highly conserved pathway in mammals that maintains organ size and homeostasis in vivo by regulating cell proliferation and apoptosis 8,9. Yes-Associated protein (YAP) is the downstream effector of the Hippo pathway, which is inactivated through its cytoplasmic retention by phosphorylation 10,11.…”