SIRT1-Mediated Deacetylation of CRABPII Regulates Cellular Retinoic Acid Signaling and Modulates Embryonic Stem Cell Differentiation

Shuang Tang; Gang Huang; Wei Fan; Yue Chen; James M. Ward; Xiaojiang Xu; Qing Xu; Ashley Kang; Michael W. McBurney; David C. Fargo; Guang Hu; Eveline Baumgart-Vogt; Yingming Zhao; Xiaoling Li

doi:10.1016/j.molcel.2014.07.011

SIRT1-Mediated Deacetylation of CRABPII Regulates Cellular Retinoic Acid Signaling and Modulates Embryonic Stem Cell Differentiation

Shuang Tang, Gang Huang, Wei Fan, Yue Chen, James M. Ward, Xiaojiang Xu, Qing Xu, Ashley Kang, Michael W. McBurney, David C. Fargo, Guang Hu, Eveline Baumgart-Vogt, Yingming Zhao, Xiaoling Li

Center for Mass Spectrometry and Proteomics

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

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.

Original language	English (US)
Pages (from-to)	843-855
Number of pages	13
Journal	Molecular Cell
Volume	55
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2014.07.011
State	Published - Sep 18 2014

Bibliographical note

Funding 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).

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© 2014 Elsevier Inc.

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Tang, S., Huang, G., Fan, W., Chen, Y., Ward, J. M., Xu, X., Xu, Q., Kang, A., McBurney, M. W., Fargo, D. C., Hu, G., Baumgart-Vogt, E., Zhao, Y., & Li, X. (2014). SIRT1-Mediated Deacetylation of CRABPII Regulates Cellular Retinoic Acid Signaling and Modulates Embryonic Stem Cell Differentiation. Molecular Cell, 55(6), 843-855. https://doi.org/10.1016/j.molcel.2014.07.011

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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.",

author = "Shuang Tang and Gang Huang and Wei Fan and Yue Chen and Ward, {James M.} and Xiaojiang Xu and Qing Xu and Ashley Kang and McBurney, {Michael W.} and Fargo, {David C.} and Guang Hu and Eveline Baumgart-Vogt and Yingming Zhao and Xiaoling Li",

note = "Funding 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). Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",

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doi = "10.1016/j.molcel.2014.07.011",

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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

N1 - Funding 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). Publisher Copyright: © 2014 Elsevier Inc.

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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SN - 1097-2765

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JO - Molecular Cell

JF - Molecular Cell

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ER -

SIRT1-Mediated Deacetylation of CRABPII Regulates Cellular Retinoic Acid Signaling and Modulates Embryonic Stem Cell Differentiation

Abstract

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