title: Oxygen-dependent acetylation and dimerization of the corepressor CtBP2 in neural stem cells.
abstract: The transcriptional corepressor CtBP2 is essential for proper development of the nervous system. The factor exerts its repression by interacting in complexes with chromatin-modifying factors such as histone deacetylases (HDAC) 1/2 and the histone demethylase LSD1/KDM1. Notably, the histone acetyl transferase p300 acetylates CtBP2 and this is an important regulatory event of the activity and subcellular localization of the protein. We recently demonstrated an essential role for CtBPs as sensors of microenvironmental oxygen levels influencing the differentiation potential of neural stem cells (NSCs), but it is not known whether oxygen levels influence the acetylation levels of CtBP factors. Here we show by using proximity ligation assay (PLA) that CtBP2 acetylation levels increased significantly in undifferentiated, proliferating NSCs under hypoxic conditions. CtBP2 interacted with the class III HDAC Sirt1 but this interaction was unaltered in hypoxic conditions, and treatment with the Sirt1 inhibitor Ex527 did not result in any significant change in total CtBP2 acetylation levels. Instead, we revealed a significant decrease in PLA signal representing CtBP2 dimerization in NSCs under hypoxic conditions, negatively correlating with the acetylation levels. Our results suggest that microenvironmental oxygen levels influence the dimerization and acetylation levels, and thereby the activity, of CtBP2 in proliferating NSCs.
authors.affiliation: Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Esra
authors.initials: E
authors.lastname: Karaca
authors.affiliation: Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jakub
authors.initials: J
authors.lastname: Lewicki
authors.affiliation: Linnaeus Center in Developmental Biology for Regenerative Medicine (DBRM), Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: Ola.Hermanson@ki.se.
authors.forename: Ola
authors.initials: O
authors.lastname: Hermanson
mesh_terms: D000107:Acetylation; D000818:Animals; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D005136:Eye Proteins / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism*; D010100:Oxygen / Q000502:physiology*; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: C486016:Ctbp2 protein, rat; D005136:Eye Proteins; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D010100:Oxygen
keywords: Cortex; Hypoxia; NSCs; Neural development; Sirt1; p53