Abstract
Abstract Inhibitors of histone deacetylases (HDACs) are of interest for treatment of MS. However, global modifications of DNA and chromatin structure are found to be associated with toxicities and adverse effects. For example, HDAC inhibitor, Trichostatin A, was capable of ameliorating the development of a mouse model of MS (EAE). However, the clinical trials in MS patients showed exacerbation of symptoms. This discrepancy may have been due to the non-specific nature produced by the drug or additional genetic changes. Thus, novel epigenetic approaches capable of targeting a specific set of genes in encephalitogenic T cells are desirable for controlling MS while minimizing adverse effects. We recently found that encephalitogenic CD4+ T cells present with a specific miRNA and HDAC signature characterized by increased expression of let-7e, HDAC-3, -5, -9 and reduced miR-140-5p and the rest of HDAC. Predicted let-7e targeted genes include HDAC-2, -10, and -11. We confirmed that let-7e regulated expression of HDAC-10. Using lentivirus or synthetic oligonucleotides to modulate the expression level of let-7e, we found that down-regulated HDAC-10 accompanied with up-regulation of acetyl-histone-3 and -4, which led to increased encephalitogenic Th1- and Th17-cell development and EAE. Our results indicated that HDAC-10 contributed to the pathogenesis of MS. Thus, use of let-7e oligonucleotides may constitute an alternative to chemical HDAC inhibitors in the treatment of MS.
Published Version
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