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Examining the effects of the histone methyltransferase inhibitor BIX-01294 on histone modifications and gene expression in both a clinical population and mouse models

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  • Kayla A Chase
  • Benjamin Feiner
  • Marcia J Ramaker
  • Edward Hu
  • Cherise Rosen
  • Rajiv P Sharma

Abstract

Schizophrenia has been consistently characterized by abnormal patterns of gene down-regulation, increased restrictive chromatin assemblies, and reduced transcriptional activity. Histone methyltransferase (HMT) mRNA and H3K9me2 levels are elevated in postmortem brain and peripheral blood cells of persons with schizophrenia. Moreover, this epigenomic state likely contributes to the disease, as HMT levels correlate with clinical symptomatology. This manuscript sought to establish the potential therapeutic value of the HMT inhibitor BIX-01294 (BIX). Human peripheral mononuclear cells (PBMC) from 24 individuals with schizophrenia and 24 healthy individuals were cultured in the presence of BIX (5uM or 10uM). Mice were given once daily intraperitoneal injections of BIX (0.5 or 1mg/kg) for one week. Cultured cells, mouse cortex, or striatum was harvested, RNA extracted and RT-PCR conducted for several schizophrenia candidate genes: IL-6, Gad1, Nanog, KLF4, Reln, and Bdnf9a. Total H3K9me2 levels were measured using western blot while H3K9me2 binding to selected genes of interest was conducted using chromatin immunoprecipitation (ChIP). Neuronal subtype-specific BDNF conditional knockdown was conducted using the cre/lox system of mutant animals. Treatment with BIX decreased H3K9me2 and increased selected mRNA levels in cultured PBMCs from both normal controls and participants with schizophrenia. In mice, peripheral administration of BIX decreased cortical H3K9me2 levels and increased schizophrenia candidate gene expression. In BDNF conditional knockdown animals, BIX administration was able to significantly rescue Bdnf9a mRNA levels in ChAT and D1 Bdnf conditional knockdown mice. The results presented in this manuscript demonstrate a potential for further research into the clinical effectiveness of histone modifying pharmacology in the treatment of schizophrenia.

Suggested Citation

  • Kayla A Chase & Benjamin Feiner & Marcia J Ramaker & Edward Hu & Cherise Rosen & Rajiv P Sharma, 2019. "Examining the effects of the histone methyltransferase inhibitor BIX-01294 on histone modifications and gene expression in both a clinical population and mouse models," PLOS ONE, Public Library of Science, vol. 14(6), pages 1-17, June.
    • Handle: RePEc:plo:pone00:0216463
    DOI: 10.1371/journal.pone.0216463
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    1. Sukanta Saha & David Chant & Joy Welham & John McGrath, 2005. "A Systematic Review of the Prevalence of Schizophrenia," PLOS Medicine, Public Library of Science, vol. 2(5), pages 1-1, May.
    2. McClave, A.K. & McKnight-Eily, L.R. & Davis, S.P. & Dube, S.R., 2010. "Smoking characteristics of adults with selected lifetime mental illnesses: Results from the 2007 national health interview survey," American Journal of Public Health, American Public Health Association, vol. 100(12), pages 2464-2472.
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