title: Epigenetic regulation of survivin by Bmi1 is cell type specific during corticogenesis and in gliomas.
abstract: Polycomb group proteins are essential regulators of stem cell function during embryonic development and in adult tissue homeostasis. Bmi1, a key component of the Polycomb Repressive Complex 1, is highly expressed in undifferentiated neural stem cells (NSC) as well as in several human cancers including high-grade gliomas--highly aggressive brain tumors. Using a conditional gene activation approach in mice, we show that overexpression of Bmi1 induces repressive epigenetic regulation of the promoter of Survivin, a well-characterized antiapoptotic protein. This phenomenon is cell type-specific and it leads to apoptotic death of progenitor cells exclusively upon commitment toward a neuronal fate. Moreover, we show that this is triggered by increased oxidative stress-induced DNA damage. In contrast, undifferentiated NSC as well as glioma-initiating cells display an open chromatin configuration at the Survivin promoter and do not undergo apoptotic death. These findings raise the possibility that normal and neoplastic stem cells depend on the same mechanism for surviving the hyperproliferative state induced by increased Bmi1 expression.
authors.affiliation: Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Serena
authors.initials: S
authors.lastname: Acquati
authors.forename: Azzura
authors.initials: A
authors.lastname: Greco
authors.forename: Danilo
authors.initials: D
authors.lastname: Licastro
authors.forename: Heeta
authors.initials: H
authors.lastname: Bhagat
authors.forename: Dario
authors.initials: D
authors.lastname: Ceric
authors.forename: Zefferino
authors.initials: Z
authors.lastname: Rossini
authors.forename: Joan
authors.initials: J
authors.lastname: Grieve
authors.forename: Maya
authors.initials: M
authors.lastname: Shaked-Rabi
authors.forename: Nick V
authors.initials: NV
authors.lastname: Henriquez
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.forename: Elia
authors.initials: E
authors.lastname: Stupka
authors.forename: Silvia
authors.initials: S
authors.lastname: Marino
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000166:cytology; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005910:Glioma / Q000235:genetics / Q000378:metabolism*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D051379:Mice; D058953:Neural Stem Cells / Q000502:physiology*; D055495:Neurogenesis; D018384:Oxidative Stress; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D054875:Ubiquitination
chemical_list: C117749:Birc5 protein, mouse; C489421:Bmi1 protein, mouse; D002843:Chromatin; D051034:Inhibitor of Apoptosis Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D000077022:Survivin; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; D063150:Polycomb Repressive Complex 1