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Transcriptional analysis of sodium valproate in a serotonergic cell line reveals gene regulation through both HDAC inhibition-dependent and independent mechanisms

The Pharmacogenomics Journal volume 21, pages 359–375 (2021)Cite this article

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Abstract

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.

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Fig. 1: Flowchart of RNA-Seq data analysis procedure.
Fig. 2: Principal component analysis of RNA-Seq normalized counts for all nine samples with the DESeq2 R package, spanned by their first two components.
Fig. 3: Flowchart for shortlisting of genes for nCounter® assay.
Fig. 4: Agreement between the four differential gene expression methods.
Fig. 5: Heatmap showing nCounter gene expression patterns for mood stabilizers and HDAC inhibitors.

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Acknowledgements

This work was supported by the Jim and Mary Carney Charitable Trust, Whangarei, New Zealand, including a Postgraduate Scholarship from this source. The RN46A cell line was a kind gift from Dr Scott Whittemore, Laboratory of Molecular Neurobiology, Louisville, Kentucky, USA.

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Authors and Affiliations

  1. Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand

    Priyanka Sinha, Simone L. Cree, Allison L. Miller, John F. Pearson & Martin A. Kennedy

  2. Carney Centre for Pharmacogenomics, University of Otago, Christchurch, New Zealand

    Priyanka Sinha, Simone L. Cree, Allison L. Miller, John F. Pearson & Martin A. Kennedy

  3. Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand

    John F. Pearson

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  1. Priyanka Sinha
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  2. Simone L. Cree
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Sinha, P., Cree, S.L., Miller, A.L. et al. Transcriptional analysis of sodium valproate in a serotonergic cell line reveals gene regulation through both HDAC inhibition-dependent and independent mechanisms. Pharmacogenomics J 21, 359–375 (2021). https://doi.org/10.1038/s41397-021-00215-x

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