Trimethylation and Acetylation of β-Catenin at Lysine 49 Represent Key Elements in ESC Pluripotency.
Wnt/β-catenin signaling is required for embryonic stem cell (ESC) pluripotency by inducing mesodermal differentiation and inhibiting neuronal differentiation; however, how β-catenin counter-regulates these differentiation pathways is unknown. Here, we show that lysine 49 (K49) of β-catenin is trimethylated (β-catMe3) by Ezh2 or acetylated (β-catAc) by Cbp. Significantly, β-catMe3 acts as a transcriptional co-repressor of the neuronal differentiation genes sox1 and sox3, whereas β-catAc acts as a transcriptional co-activator of the key mesodermal differentiation gene t-brachyury (t-bra). Furthermore, β-catMe3 and β-catAc are alternatively enriched on repressed or activated genes, respectively, during ESC and adult stem cell differentiation into neuronal or mesodermal progenitor cell lineages. Importantly, expression of a β-catenin K49A mutant results in major defects in ESC differentiation. We conclude that β-catenin K49 trimethylation and acetylation are key elements in regulating ESC pluripotency and differentiation potential.
Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Emeritus Laboratory Rolf Kemler, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Katrin
K
Hoffmeyer
University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland.
Dirk
D
Junghans
Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Transgenic Mouse Unit, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Benoit
B
Kanzler
Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Emeritus Laboratory Rolf Kemler, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany. Electronic address: kemler@ie-freiburg.mpg.de.
Rolf
R
Kemler
D000107:Acetylation; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism; D005786:Gene Expression Regulation; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D009154:Mutation / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011917:Rats, Inbred Lew; D051176:beta Catenin / Q000737:chemistry* / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D051176:beta Catenin; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine
PRC2; Wnt signaling; gene repression; methylation; mouse embryonic stem cells; β-catenin