Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
Carney Centre for Pharmacogenomics, University of Otago, Christchurch, New Zealand.
Pharmacogenomics J. 2021 Jun;21(3):359-375. doi: 10.1038/s41397-021-00215-x. Epub 2021 Mar 1.
Sodium valproate (VPA) is a histone deacetylase (HDAC) inhibitor, widely prescribed in the treatment of bipolar disorder, and yet the precise modes of therapeutic action for this drug are not fully understood. After exposure of the rat serotonergic cell line RN46A to VPA, RNA-sequencing (RNA-Seq) analysis showed widespread changes in gene expression. Analysis by four bioinformatic pipelines revealed as many as 230 genes were significantly upregulated and 72 genes were significantly downregulated. A subset of 23 differentially expressed genes was selected for validation using the nCounter® platform, and of these we obtained robust validation for ADAM23, LSP1, MAOB, MMP13, PAK3, SERPINB2, SNAP91, WNT6, and ZCCHC12. We investigated the effect of lithium on this subset and found four genes, CDKN1C, LSP1, SERPINB2, and WNT6 co-regulated by lithium and VPA. We also explored the effects of other HDAC inhibitors and the VPA analogue valpromide on the subset of 23 selected genes. Expression of eight of these genes, CDKN1C, MAOB, MMP13, NGFR, SHANK3, VGF, WNT6 and ZCCHC12, was modified by HDAC inhibition, whereas others did not appear to respond to several HDAC inhibitors tested. These results suggest VPA may regulate genes through both HDAC-dependent and independent mechanisms. Understanding the broader gene regulatory effects of VPA in this serotonergic cell model should provide insights into how this drug works and whether other HDAC inhibitor compounds may have similar gene regulatory effects, as well as highlighting molecular processes that may underlie regulation of mood.
丙戊酸钠（VPA）是一种组蛋白去乙酰化酶（HDAC）抑制剂，广泛用于治疗双相情感障碍，但这种药物的确切治疗作用机制尚未完全阐明。在将大鼠 5-羟色胺能细胞系 RN46A 暴露于 VPA 后，RNA 测序（RNA-Seq）分析显示基因表达广泛变化。通过四个生物信息学管道的分析显示，多达 230 个基因显著上调，72 个基因显著下调。选择了一组 23 个差异表达基因使用 nCounter®平台进行验证，其中 ADAM23、LSP1、MAOB、MMP13、PAK3、SERPINB2、SNAP91、WNT6 和 ZCCHC12 的表达得到了稳健的验证。我们研究了锂对这一组基因的影响，发现锂和 VPA 共调控了四个基因 CDKN1C、LSP1、SERPINB2 和 WNT6。我们还探索了其他 HDAC 抑制剂和 VPA 类似物 valpromide 对这一组 23 个选定基因的影响。这 8 个基因 CDKN1C、MAOB、MMP13、NGFR、SHANK3、VGF、WNT6 和 ZCCHC12 的表达受 HDAC 抑制调节，而其他基因似乎对几种测试的 HDAC 抑制剂没有反应。这些结果表明，VPA 可能通过 HDAC 依赖和非依赖的机制调节基因。了解 VPA 在这种 5-羟色胺能细胞模型中的更广泛的基因调控作用，应该能够深入了解这种药物的作用机制，以及其他 HDAC 抑制剂化合物是否可能具有类似的基因调控作用，并突出可能调节情绪的分子过程。
