Histone acetylation in astrocytes suppresses GFAP and stimulates a reorganization of the intermediate filament network

Regina Kanski, Marjolein A M Sneeboer, Emma J van Bodegraven, Jacqueline A Sluijs, Wietske Kropff, Marit W. Vermunt, Menno P Creyghton, Lidia De Filippis, Angelo Vescovi, Eleonora Aronica, P. van Tijn, Miriam E van Strien, Elly M Hol

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Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)4368-80
Aantal pagina's13
TijdschriftJournal of Cell Science
Volume127
Nummer van het tijdschriftPt 20
DOI's
StatusGepubliceerd - 15 okt 2014

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