Transcription of genes encoding synaptic vesicle proteins in human neural stem cells: chromatin accessibility, histone methylation pattern, and the essential role of rest.
Human HNSC.100 neural stem cells up-regulate expression of GFAP following withdrawal of mitogens. Activation of the ERK signaling pathway prevented the up-regulation of GFAP expression. Incubation of cells with retinoic acid in the absence of mitogens enhanced basal neuronal differentiation that was accompanied by an up-regulation of neuronal gene expression and a down-regulation of GFAP and nestin expression. Retinoic acid treatment changed the histone code of neuronal genes encoding synapsin I, synaptophysin, and synaptotagmins II, IV, and VII from a transcriptionally inactive (methylation of lysine residue 9 of histone 3) to a transcriptionally active state (methylation of lysine residue 4 of histone 3). In contrast, the chromatin structure of the GFAP gene is transformed from a transcriptionally active state in unstimulated neural stem cells to a transcriptionally inactive state in retinoic acid-stimulated cells. Additionally, retinoic acid treatment reduced the binding of histone deacetylase-1 and REST to neuronal genes. The inhibition of histone deacetylase activity induced expression of genes encoding synaptic vesicle proteins in unstimulated neural stem cells. Similarly, neuronal gene transcription was enhanced following expression of a mutant of REST that contained a transcriptional activation domain. These data indicate that in undifferentiated human neural stem cells, neuronal genes encoding synaptic vesicle proteins are accessible for the REST mutant and are sensitive to enhanced histone acetylation.
Ekici
Myriam
M
Department of Medical Biochemistry and Molecular Biology, University of Saarland Medical Center, Homburg, Germany.
Hohl
Mathias
M
Schuit
Frans
F
Martínez-Serrano
Alberto
A
Thiel
Gerald
G
D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008745:Methylation / Q000187:drug effects; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology; D000099229:RE1-Silencing Transcription Factor
D000970:Antineoplastic Agents; D002843:Chromatin; D048049:Extracellular Signal-Regulated MAP Kinases; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D006657:Histones; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D014212:Tretinoin; D000099229:RE1-Silencing Transcription Factor; C110550:HDAC1 protein, human