Valproic Acid and Other HDAC Inhibitors Upregulate FGF21 Gene Expression and Promote Process Elongation in Glia by Inhibiting HDAC2 and 3
Valproic Acid and Other HDAC Inhibitors Upregulate FGF21 Gene Expression and Promote Process Elongation in Glia by Inhibiting HDAC2 and 3
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DOI：
10.1093/ijnp/pyw035
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发表时间：
2016-08-01
影响因子：
4.8
通讯作者：
Chuang, De-Maw
中科院分区：
文献类型：
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作者：
Leng, Yan;Wang, Junyu;Chuang, De-Maw
成纤维细胞生长因子21是一种新型的葡萄糖和脂质代谢调节剂，在神经元中具有强大的保护作用。然而，其在胶质细胞中的表达和功能尚不清楚。丙戊酸是一种情绪稳定剂和抗惊厥药，是一种组蛋白去乙酰化酶抑制剂和动态基因调节剂。我们研究了组蛋白去乙酰化酶抑制剂丙戊酸和其他抑制剂是否上调成纤维细胞生长因子21的表达，如果是这样，试图确定组蛋白去乙酰化酶亚型（S）参与和他们的作用，改变胶质细胞形态。C6胶质瘤或原代皮质胶质细胞培养物与组蛋白去乙酰化酶抑制剂处理，成纤维细胞生长因子21水平和细胞突起的长度随后进行了测量。组蛋白去乙酰化酶1，2或3也被敲低，以检测哪种亚型参与调节成纤维细胞生长因子21 mRNA水平。最后，敲低和过度表达的成纤维细胞生长因子21进行，以确定它是否发挥了作用，在调节细胞过程length.Treatment的C6细胞或原代胶质细胞培养物与丙戊酸升高成纤维细胞生长因子21的mRNA水平，延长细胞过程的长度，并显着增加乙酰化组蛋白-H3的水平。其他组蛋白去乙酰化酶抑制剂，包括泛和I类特异性抑制剂，或选择性敲低组蛋白去乙酰化酶2或3亚型产生类似的效果。敲低或过表达成纤维细胞生长因子21分别显著减少或增加C6细胞突起长度，在胶质细胞系和原代胶质细胞中，使用药理学抑制和选择性组蛋白去乙酰化酶基因沉默来提高成纤维细胞生长因子21 mRNA水平导致细胞突起延长。我们的研究提供了一个新的机制，通过组蛋白去乙酰化酶2和3参与上调成纤维细胞生长因子21的转录和延长过程中的胶质细胞生长。
Fibroblast growth factor 21, a novel regulator of glucose and lipid metabolism, has robust protective properties in neurons. However, its expression and function in glia are unknown. Valproic acid, a mood stabilizer and anticonvulsant, is a histone deacetylase inhibitor and a dynamic gene regulator. We investigated whether histone deacetylase inhibition by valproic acid and other inhibitors upregulates fibroblast growth factor 21 expression and, if so, sought to identify the histone deacetylase isoform(s) involved and their role in altering glial cell morphology.C6 glioma or primary cortical glial cultures were treated with histone deacetylase inhibitors, and fibroblast growth factor 21 levels and length of cell processes were subsequently measured. Histone deacetylase 1, 2, or 3 was also knocked down to detect which isoform was involved in regulating fibroblast growth factor 21 mRNA levels. Finally, knockdown and overexpression of fibroblast growth factor 21 were performed to determine whether it played a role in regulating cell process length.Treatment of C6 cells or primary glial cultures with valproic acid elevated fibroblast growth factor 21 mRNA levels, extended cell process length, and markedly increased acetylated histone-H3 levels. Other histone deacetylase inhibitors including pan- and class I-specific inhibitors, or selective knockdown of histone deacetylase 2 or 3 isoform produced similar effects. Knockdown or overexpression of fibroblast growth factor 21 significantly decreased or increased C6 cell process length, respectively.In glial cell line and primary glia, using pharmacological inhibition and selective gene silencing of histone deacetylases to boost fibroblast growth factor 21 mRNA levels results in elongation of cell processes. Our study provides a new mechanism via which histone deacetylase 2 and 3 participate in upregulating fibroblast growth factor 21 transcription and extending process outgrowth in glia.