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.
Bibliographical noteFunding Information:
We thank Drs. Paul Wade and Raja Jothi and members of the Li laboratory for critical reading of the manuscript. We would also like to thank Dr. Sue Edelstein from the NIEHS Photography & Graphics Service Center for the cartoon graph of Figure S7 A and the graphical abstract; Ms. Julie Foley from the NIEHS Cellular & Molecular Pathology Branch for histological analyses of mouse embryos; and Mr. C. Jeff Tucker and Dr. Agnes Janoshazi from NIEHS Fluorescence Microscopy and Imaging Center for quantification of confocal images. This research was supported by the Intramural Research Program of National Institute of Environmental Health Sciences of the NIH to X.L. (Z01 ES102205) and by NIH grants to Y.Z. (GM105933 and CA160036). S.T. was supported by a predoctoral fellowship from Shanghai Jiao Tong University and by a research grant to G.H. (New Drug Discovery Project, 2012ZX09506-001-005).