Histone Deacetylase Inhibition-Mediated Neuronal Differentiation of Multipotent Adult Neural Progenitor Cells

It has become apparent that chromatin modification plays a critical role in the regulation of cell-type-specific gene expression. Here, we show that an inhibitor of histone deacetylase, valproic acid (VPA), induced neuronal differentiation of adult hippocampal neural progenitors. In addition, VPA in...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 101; no. 47; pp. 16659 - 16664
Main Authors Hsieh, Jenny, Nakashima, Kinichi, Kuwabara, Tomoko, Mejia, Eunice, Gage, Fred H.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 23.11.2004
National Acad Sciences
Subjects
Acetylation
Animals
Astrocytes
Astrocytes - cytology
Astrocytes - drug effects
Astrocytes - enzymology
Basic Helix-Loop-Helix Transcription Factors
Biological Sciences
Cell Differentiation - drug effects
Cells, Cultured
Chromatin
Cultured cells
Enzyme Inhibitors - pharmacology
Gene expression
Gene Expression - drug effects
Histone Deacetylase Inhibitors
Histones
Mice
Multipotent Stem Cells - cytology
Multipotent Stem Cells - drug effects
Multipotent Stem Cells - enzymology
Nerve Tissue Proteins - genetics
Neural stem cells
Neurology
Neurons
Neurons - cytology
Neurons - drug effects
Neurons - enzymology
Oligodendroglia
Oligodendroglia - cytology
Oligodendroglia - drug effects
Oligodendroglia - enzymology
Progenitor cells
Rats
Valproic Acid - pharmacology
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Summary:It has become apparent that chromatin modification plays a critical role in the regulation of cell-type-specific gene expression. Here, we show that an inhibitor of histone deacetylase, valproic acid (VPA), induced neuronal differentiation of adult hippocampal neural progenitors. In addition, VPA inhibited astrocyte and oligodendrocyte differentiation, even in conditions that favored lineage-specific differentiation. Among the VPA-up-regulated, neuron-specific genes, a neurogenic basic helix-loop-helix transcription factor, NeuroD, was identified. Overexpression of NeuroD resulted in the induction and suppression of neuronal and glial differentiation, respectively. These results suggest that VPA promotes neuronal fate and inhibits glial fate simultaneously through the induction of neurogenic transcription factors including NeuroD.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
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To whom correspondence may be addressed. E-mail: gage@salk.edu or kin@bs.naist.jp.
Abbreviations: HDAC, histone deacetylase; VPA, valproic acid; TSA, trichostatin A; NRSF/REST, neuron-restrictive silencer factor/repressor element-1 silencing transcription factor; ERK, extracellular signal-regulated kinase; bHLH, basic helix–loop–helix; NaB, sodium butyrate; MAP2ab, microtubule-associated proteins 2a and 2b; GFAP, glial fibrillary acidic protein; FGF-2, fibroblast growth factor 2; IGF-1, insulin-like growth factor 1; STAT3, signal transducer and activator of transcription 3; BMP-2, bone morphogenetic protein 2; LIF, leukemia inhibitory factor; SGZ, subgranular zone.
Contributed by Fred H. Gage, October 15, 2004
J.H. and K.N. contributed equally to this work.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0407643101