Yu In Tag, Park Jin-Yong, Kim Sung Hyun, Lee Jeong-Sik, Kim Yong-Seok, Son Hyeon
Department of Biochemistry and Molecular Biology, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea.
Neuropharmacology. 2009 Feb;56(2):473-80. doi: 10.1016/j.neuropharm.2008.09.019. Epub 2008 Nov 1.
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.
丙戊酸盐（VPA）会影响神经元细胞的增殖和分化。然而，对于诸如基因转录改变等与细胞命运选择相关的下游事件，我们却知之甚少。为了确定VPA在海马神经发生过程中的细胞命运选择中是否发挥指导作用，我们研究了参与细胞周期和神经元分化的基因的表达情况。在祖细胞阶段用VPA处理会导致细胞增殖受到强烈抑制以及神经元分化的诱导，同时伴有神经前体转录因子表达的增加和神经元细胞数量的增多。Ngn1、Math1和p15表达的增加表明，在对组蛋白去乙酰化酶抑制剂（HDACi）的反应中，细胞命运向神经元方向转变。染色质免疫沉淀（ChIP）分析表明，在培养的海马神经祖细胞中，乙酰化组蛋白H4（Ac - H4）与Ngn1、Math1和p15启动子相关联。VPA诱导的海马神经发生还伴随着在海马提取物中Ac - H4与Ngn1启动子的关联。HDACi与Ngn1、Math1和p15启动子之间关联的发现扩展了HDAC抑制作为转录水平上神经元分化关键调节因子的重要性。
