title: SIRT1-mediated deacetylation of CRABPII regulates cellular retinoic acid signaling and modulates embryonic stem cell differentiation.
abstract: 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.
authors.affiliation: Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Tang
authors.affiliation: Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: huang2802@163.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.affiliation: Division of Medical Cell Biology, Institute for Anatomy and Cell Biology II, Justus Liebig University, Aulweg 123, 35385 Giessen, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Fan
authors.affiliation: The Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Integrated Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Ward
authors.affiliation: Integrated Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Xu
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; NIEHS Scholars Connect Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Kang
authors.affiliation: Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6.
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.affiliation: Integrated Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Fargo
authors.affiliation: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Hu
authors.affiliation: Division of Medical Cell Biology, Institute for Anatomy and Cell Biology II, Justus Liebig University, Aulweg 123, 35385 Giessen, Germany.
authors.forename: Eveline
authors.initials: E
authors.lastname: Baumgart-Vogt
authors.affiliation: The Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. Electronic address: lix3@niehs.nih.gov.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism*; D059647:Gene-Environment Interaction; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D056564:Sirtuin 1