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Understanding the function of histone modifications across inducible genes in mammalian cells requires quantitative, comparative analysis of their fate during gene activation and identification of enzymes responsible. We produced high-resolution comparative maps of the distribution and dynamics of H3K4me3, H3K36me3, H3K79me2 and H3K9ac across c-fos and c-jun upon gene induction in murine fibroblasts. In unstimulated cells, continuous turnover of H3K9 acetylation occurs on all K4-trimethylated histone H3 tails; distribution of both modifications coincides across promoter and 5' part of the coding region. In contrast, K36- and K79-methylated H3 tails, which are not dynamically acetylated, are restricted to the coding regions of these genes. Upon stimulation, transcription-dependent increases in H3K4 and H3K36 trimethylation are seen across coding regions, peaking at 5' and 3' ends, respectively. Addressing molecular mechanisms involved, we find that Huntingtin-interacting protein HYPB/Setd2 is responsible for virtually all global and transcription-dependent H3K36 trimethylation, but not H3K36-mono- or dimethylation, in these cells. These studies reveal four distinct layers of histone modification across inducible mammalian genes and show that HYPB/Setd2 is responsible for H3K36 trimethylation throughout the mouse nucleus.

Stably enhanced histone acetylation has long been regarded as a condition of transcriptionally active genes. Recent papers suggest a more dynamic model, with rapid turnover of acetylation observed at nontranscribing "poised" genes and shown to be an important determinant of transcriptional efficiency upon gene induction. Are these "special cases," restricted to specific genes and specific types of histone modifications, or could the entire panoply of histone modifications associated with transcription now be revisited with a much more dynamic perspective?

The phosphorylation and acetylation (phosphoacetylation) of histone H3 tails concomitant with gene activation is now well established and has been observed at several inducible genes. However, two aspects of this response have been controversial. The first relates to the identity of the kinase that phosphorylates histone H3. Experiments with Coffin-Lowry cells purporting to show that Rsk2 was the histone H3 kinase have proven to be irreproducible. The second relates to the proposition that histone H3 phosphorylation and acetylation are 'synergistic and coupled' in mammalian cells. But here too, some of the experiments have not been reproducible and some of the key statements contaminated by issues of antibody specificity. More recent studies indicate that H3 phosphorylation and acetylation are independently targeted to the same histone H3 tail.