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Keywords:

  • cochlear explant;
  • gentamicin;
  • histone acetyl transferase;
  • histone deacetylase inhibitors;
  • ototoxicity

Abstract

Post-translational modification of histones is an important form of chromatin regulation impacting transcriptional activation. Histone acetyltransferases, for example, acetylate lysine residues on histone tails thereby enhancing gene transcription, while histone deacetylases (HDACs) remove those acetyl groups and repress gene transcription. Deficient histone acetylation is associated with pathologies, and histone deacetylase inhibitors have been studied in the treatment of cancer and neurodegenerative diseases. Here we explore histone acetylation in cochlear sensory cells following a challenge with gentamicin, an aminoglycoside antibiotic known to cause loss of auditory hair cells and hearing. The addition of the drug to organotypic cultures of the mouse organ of Corti decreased the acetylation of histone core proteins (H2A Ack5, H2B Ack12, H3 Ack9, and H4 Ack8) followed by a loss of sensory cells. Protein levels of HDAC1, HDAC3 and HDAC4 were increased while the histone acetyltransferases such as CREB-binding protein and p300 remained unchanged. We next hypothesized that protecting histone acetylation should prevent cell death and tested the effects of HDAC-inhibitors on the actions of gentamicin. Co-treatment with trichostatin A maintained near-normal levels of acetylation of histone core proteins in cochlear hair cells and attenuated gentamicin-induced cell death. The addition of sodium butyrate also rescued hair cells from damage by gentamicin. The results are consistent with an involvement of deficient histone acetylation in aminoglycoside-induced hair cell death and point to the potential value of HDAC-inhibitors in protection from the side effects of these drugs.