Histone deacetylase inhibitors increase neuronal differentiation in adult forebrain precursor cells.
Chromatin modification plays a key role in fate decision of neural stem cells. Here, we explored the impact of epigenetic remodelling onto neuronal fate determination using specific inhibitors of histone deacetylases (iHDAC). Adult subventricular zone (SVZ) precursor cells were expanded as neurospheres and treated in vitro with second generation iHDAC MS-275, M344 and suberoylanilide hydroxamic acid (SAHA). All tested compounds revealed a significant increase of betaIII-tubulin positive neurons (ranging from 258 to 431%) in a concentration-dependent manner. The number of oligodendrocytes was decreased by almost 50%, accompanied by a reduction of Olig2 mRNA expression. In contrast, astrocyte quantity remained unaffected after iHDAC treatment. Both control and iHDAC treated cells expressed markers of mature GABAergic and dopaminergic neurons. Increased expression levels of NeuroD, Cyclin D2 and B-lymphocyte translocation gene 3 (Btg3) point to a shift towards neuronal fate determination targeted by HDAC inhibitors.
Siebzehnrubl
Florian A
FA
Department of Neuropathology, University of Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054, Erlangen, Germany. fs@neuropatho.imed.uni-erlangen.de
Buslei
Rolf
R
Eyupoglu
Ilker Y
IY
Seufert
Sebastian
S
Hahnen
Eric
E
Blumcke
Ingmar
I
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D018874:Spheroids, Cellular; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D004298:Dopamine; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D014404:Tubulin; D005680:gamma-Aminobutyric Acid; C512773:Olig2 protein, mouse