Deacetylation of H4-K16Ac and heterochromatin assembly in senescence

We found that both deacetylation of H4-K16Ac and expression of HMGA1/2 can contribute to DNA compaction during senescence. SIRT2, an NAD-dependent class III histone deacetylase, contributes to H4-K16Ac deacetylation and DNA compaction in human fibroblast cell lines that assemble striking senescence-associated heterochromatin foci (SAHFs). Decreased H4-K16Ac was observed in both replicative and oncogene-induced senescence of these cells. In contrast, this mechanism was inoperative in a fibroblast cell line that did not assemble extensive heterochromatin during senescence. Treatment of senescent cells with trichostatin A, a class I/II histone deacetylase inhibitor, also induced rapid and reversible decondensation of SAHFs. Inhibition of DNA compaction did not significantly affect the stability of the senescent state.Variable DNA compaction observed during senescence is explained in part by cell-type specific regulation of H4 deacetylation and HMGA1/2 expression. Deacetylation of H4-K16Ac during senescence may explain reported decreases in this mark during mammalian aging and in cancer cells.Genomic DNA in eukaryotes is packaged into chromatin. The histones and non-histone proteins of chromatin compact the DNA and govern its accessibility to enzymes during transcription, replication, repair and recombination. Poorly transcribed regions of the genome are typically found in highly compacted DNA as heterochromatin, whereas transcribed sequences are found in the more accessible euchromatin [1]. Post-translational modifications of histones represent an important mechanism modulating the accessibility of chromatin and contributing to the recruitment of other proteins to chromatin [2]. Histones are extensively modified principally by acetylation, methylation, ubiquitylation, and phosphorylation. Euchromatin is enriched in histones acetylated at lysine residues. Acetylation of H4-K16 plays a particularly important, evolutionarily conserved role in regulating chromatin compacti