In vitro ischemia decreases histone H4K16 acetylation in neural cells

• A drastic decrease of H4K16Ac upon in vitro ischemia in neural cells was found.
• H4K16Ac decrease is affected by histone deacetylases and mitochondrial acetyl-CoA.
• H4K16Ac decrease displays cell specific effects on gene expression.

Inhibitors of histone deacetylases are frequently used against ischemia-induced injury, but the specific mechanisms of their action are poorly understood. Here, we report that following a 5–7-h oxygen–glucose deprivation (OGD) acetylation of histone H4 at residue K16 (H4K16Ac) decreases by 40–80% in both PC12 cells and primary neurons. This effect can be reverted by treatment with trichostatin A, or by supplementation with acetyl-CoA. A decrease in H4K16Ac levels can affect the expression of mitochondrial uncoupling protein 2 (UCP2), huntingtin-interacting protein 1 (HIP1) and Notch-pathway genes in a cell-specific manner. Thus, H4K16 acetylation is important for responses to ischemia and cell energy stress, and depends on both cytosolic and mitochondrial acetyl-CoA.