title: Histone acetylation in astrocytes suppresses GFAP and stimulates a reorganization of the intermediate filament network.
abstract: Glial fibrillary acidic protein (GFAP) is the main intermediate filament in astrocytes and is regulated by epigenetic mechanisms during development. We demonstrate that histone acetylation also controls GFAP expression in mature astrocytes. Inhibition of histone deacetylases (HDACs) with trichostatin A or sodium butyrate reduced GFAP expression in primary human astrocytes and astrocytoma cells. Because splicing occurs co-transcriptionally, we investigated whether histone acetylation changes the ratio between the canonical isoform GFAPα and the alternative GFAPδ splice variant. We observed that decreased transcription of GFAP enhanced alternative isoform expression, as HDAC inhibition increased the GFAPδ∶GFAPα ratio. Expression of GFAPδ was dependent on the presence and binding of splicing factors of the SR protein family. Inhibition of HDAC activity also resulted in aggregation of the GFAP network, reminiscent of our previous findings of a GFAPδ-induced network collapse. Taken together, our data demonstrate that HDAC inhibition results in changes in transcription, splicing and organization of GFAP. These data imply that a tight regulation of histone acetylation in astrocytes is essential, because dysregulation of gene expression causes the aggregation of GFAP, a hallmark of human diseases like Alexander's disease.
authors.affiliation: Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
authors.forename: Regina
authors.initials: R
authors.lastname: Kanski
authors.affiliation: Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
authors.forename: Marjolein A M
authors.initials: MA
authors.lastname: Sneeboer
authors.affiliation: Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: van Bodegraven
authors.affiliation: Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Sluijs
authors.affiliation: Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
authors.forename: Wietske
authors.initials: W
authors.lastname: Kropff
authors.affiliation: Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584CT, Utrecht, The Netherlands.
authors.forename: Marit W
authors.initials: MW
authors.lastname: Vermunt
authors.affiliation: Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584CT, Utrecht, The Netherlands.
authors.forename: Menno P
authors.initials: MP
authors.lastname: Creyghton
authors.affiliation: Department of Biotechnologies, Fondazione Centro San Raffaele del Monte Tabor, 20132 Milan, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: De Filippis
authors.affiliation: Department of Biotechnologies, Fondazione Centro San Raffaele del Monte Tabor, 20132 Milan, Italy Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo (FG), Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Vescovi
authors.affiliation: Department of Neuropathology, Academic Medical Center, University of Amsterdam (UvA), 1105 AZ Amsterdam, The Netherlands SEIN - Stichting Epilepsie Instellingen Nederland, 2103 SW Heemstede, The Netherlands Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, 1090 GE Amsterdam, The Netherlands.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.affiliation: Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands Hubrecht Institute, an Institute of the Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, 3508 AD Utrecht, The Netherlands.
authors.forename: Paula
authors.initials: P
authors.lastname: van Tijn
authors.affiliation: Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
authors.forename: Miriam E
authors.initials: ME
authors.lastname: van Strien
authors.affiliation: Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, 1090 GE Amsterdam, The Netherlands Department of Translational Neuroscience, Brain Center Rudolf Magus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CX, Utrecht, The Netherlands e.m.hol-2@umcutrecht.nl.
authors.forename: Elly M
authors.initials: EM
authors.lastname: Hol
mesh_terms: D000107:Acetylation / Q000187:drug effects; D038261:Alexander Disease / Q000235:genetics / Q000378:metabolism*; D017398:Alternative Splicing / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D020148:Butyric Acid / Q000494:pharmacology; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D066329:Protein Aggregates; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects
chemical_list: D005904:Glial Fibrillary Acidic Protein; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D066329:Protein Aggregates; D020033:Protein Isoforms; D020148:Butyric Acid; C012589:trichostatin A; D006655:Histone Deacetylases
keywords: Alternative splicing; Astrocytes; Epigenetics; GFAP isoforms; Neural stem cells