TY - JOUR
T1 - SIRT1-Mediated Deacetylation of CRABPII Regulates Cellular Retinoic Acid Signaling and Modulates Embryonic Stem Cell Differentiation
AU - Tang, Shuang
AU - Huang, Gang
AU - Fan, Wei
AU - Chen, Yue
AU - Ward, James M.
AU - Xu, Xiaojiang
AU - Xu, Qing
AU - Kang, Ashley
AU - McBurney, Michael W.
AU - Fargo, David C.
AU - Hu, Guang
AU - Baumgart-Vogt, Eveline
AU - Zhao, Yingming
AU - Li, Xiaoling
PY - 2014/9/18
Y1 - 2014/9/18
N2 - Retinoid homeostasis is critical for normal embryonic development. Both the deficiency and excess of these compounds are associated with congenital malformations. Here we demonstrate that SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, contributes to homeostatic retinoic acid (RA) signaling and modulates mouse embryonic stem cell (mESC) differentiation in part through deacetylation of cellular retinoic acid binding protein II (CRABPII). We show that RA-mediated acetylation of CRABPII at K102 is essential for its nuclear accumulation and subsequent activation of RA signaling. SIRT1 interacts with and deacetylates CRABPII, regulating its subcellular localization. Consequently, SIRT1 deficiency induces hyperacetylation and nuclear accumulation of CRABPII, enhancing RA signaling and accelerating mESC differentiation in response to RA. Consistently, SIRT1 deficiency is associated with elevated RA signaling and development defects in mice. Our findings reveal a molecular mechanism that regulates RA signaling and highlight the importance of SIRT1 in regulation of ESC pluripotency and embryogenesis.
AB - Retinoid homeostasis is critical for normal embryonic development. Both the deficiency and excess of these compounds are associated with congenital malformations. Here we demonstrate that SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, contributes to homeostatic retinoic acid (RA) signaling and modulates mouse embryonic stem cell (mESC) differentiation in part through deacetylation of cellular retinoic acid binding protein II (CRABPII). We show that RA-mediated acetylation of CRABPII at K102 is essential for its nuclear accumulation and subsequent activation of RA signaling. SIRT1 interacts with and deacetylates CRABPII, regulating its subcellular localization. Consequently, SIRT1 deficiency induces hyperacetylation and nuclear accumulation of CRABPII, enhancing RA signaling and accelerating mESC differentiation in response to RA. Consistently, SIRT1 deficiency is associated with elevated RA signaling and development defects in mice. Our findings reveal a molecular mechanism that regulates RA signaling and highlight the importance of SIRT1 in regulation of ESC pluripotency and embryogenesis.
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UR - http://www.scopus.com/inward/citedby.url?scp=84907983116&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2014.07.011
DO - 10.1016/j.molcel.2014.07.011
M3 - Article
C2 - 25155613
AN - SCOPUS:84907983116
VL - 55
SP - 843
EP - 855
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 6
ER -