Valproic acid promotes neuronal differentiation by induction of proneural factors in association with H4 acetylation.
Valproate (VPA) influences the proliferation and differentiation of neuronal cells. However, little is known about the downstream events, such as alterations in gene transcription, that are associated with cell fate choice. To determine whether VPA plays an instructive role in cell fate choice during hippocampal neurogenesis, the expression of genes involved in the cell cycle and neuronal differentiation was investigated. Treatment with VPA during the progenitor stages resulted in strong inhibition of cell proliferation and induction of neuronal differentiation, accompanied by increases in the expression of proneural transcription factors and in neuronal cell numbers. The increased expression of Ngn1, Math1 and p15 points to a shift towards neuronal fate in response to histone deacetylase inhibitors (HDACi). Chromatin immunoprecipitation (ChIP) analysis showed that acetylated histone H4 (Ac-H4) was associated with the Ngn1, Math1 and p15 promoters in cultured hippocampal neural progenitor cells. VPA-induced hippocampal neurogenesis was also accompanied by association of Ac-H4 with the Ngn1 promoter in hippocampal extracts. The discovery of an association between HDACi and the Ngn1, Math1 and p15 promoters extends the importance of HDAC inhibition as a key regulator of neuronal differentiation at the transcriptional level.
Yu
In Tag
IT
Department of Biochemistry and Molecular Biology, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea.
Park
Jin-Yong
JY
Kim
Sung Hyun
SH
Lee
Jeong-Sik
JS
Kim
Yong-Seok
YS
Son
Hyeon
H
D000107:Acetylation / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D006657:Histones / Q000378:metabolism*; D020287:In Situ Nick-End Labeling / Q000379:methods; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology*
D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D004791:Enzyme Inhibitors; D006657:Histones; D009419:Nerve Tissue Proteins; D014635:Valproic Acid; C510879:neurogenin-1, rat