Inhibition of histone deacetylase activity induces developmental plasticity in oligodendrocyte precursor cells.
Recently, it was demonstrated that lineage-committed oligodendrocyte precursor cells (OPCs) can be converted to multipotent neural stem-like cells, capable of generating both neurons and glia after exposure to bone morphogenetic proteins. In an effort to understand and control the developmental plasticity of OPCs, we developed a high-throughput screen to identify novel chemical inducers of OPC reprogramming. Using this system, we discovered that inhibition of histone deacetylase (HDAC) activity in OPCs acts as a priming event in the induction of developmental plasticity, thereby expanding the differentiation potential to include the neuronal lineage. This conversion was found to be mediated, in part, through reactivation of sox2 and was highly reproducible at the clonal level. Further, genome-wide expression analysis demonstrated that HDAC inhibitor treatment activated sox2 and 12 other genes that identify or maintain the neural stem cell state while simultaneously silencing a large group of oligodendrocyte lineage-specific genes. This series of experiments demonstrates that global histone acetylation, induced by HDAC inhibition, can partially reverse the lineage restriction of OPCs, thereby inducing developmental plasticity.
Lyssiotis
Costas A
CA
The Skaggs Institute of Chemical Biology and Department of Chemistry, The Scripps Research Institute, 10550 North Torry Pines Road, La Jolla, CA 92037, USA.
Walker
John
J
Wu
Chunlei
C
Kondo
Toru
T
Schultz
Peter G
PG
Wu
Xu
X
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000254:growth & development; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D046228:Microarray Analysis; D008954:Models, Biological; D039902:Multipotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D009836:Oligodendroglia / Q000166:cytology* / Q000201:enzymology / Q000502:physiology; D011401:Promoter Regions, Genetic; D051381:Rats; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D024002:HMGB Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D055748:SOXB1 Transcription Factors; C527784:Sox2 protein, rat; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D006655:Histone Deacetylases