Nickel compounds are novel inhibitors of histone H4 acetylation

Environmental factors influence carcinogenesis by interfering with a variet y of cellular targets. Carcinogenic nickel compounds, although generally in active in most gene mutation assays, induce chromosomal damage in heterochr omatic regions and cause silencing of reporter genes when they are located near telomere or heterochromatin in either yeast or mammalian cells. We stu died the effects of nickel on the lysine acetylation status of the NH2-term inal region of histone H4. At nontoxic levels, nickel decreased the levels of histone H4 acetylation in vivo in both yeast and mammalian cells, affect ing only lysine 12 in mammalian cells and all of the four lysine residues i n yeast. In yeast, lysine 12 and 16 were more greatly affected than lysine 5 and 8, Interestingly, a histidine Ni2+ anchoring site is found at positio n 18 from the NH2-terminal tail of H4. Nickel was also found to inhibit the acetylation of H4 in vitro using purified recombinant histone acetyltransf erase. To our knowledge, this is the first agent shown to decrease histone H4 acetylation at nontoxic levels.