MITOGEN-STIMULATED PHOSPHORYLATION OF HISTONE H3 IS TARGETED TO A SMALL HYPERACETYLATION-SENSITIVE FRACTION

Diverse agents, including growth factors and phorbol esters, induce ra pid transcriptional activation of a subset of immediate-early (IE) gen es that include the protooncogenes c-fos and c-jun. Among the earliest nuclear signaling events concomitant with IE gene activation is the p hosphorylation of nucleosomal histone H3 in its basically charged N-te rminal tail. This highly conserved domain is also subject to reversibl e posttranslational acetylation at specific lysine residues, a process implicated in transcriptional regulation. We show here that H3 phosph orylation associated with G(0)-G(1) transition affects only a small fr action of this histone in the nucleus. Moreover, this fraction is bioc hemically distinct from bulk H3 in being extremely sensitive to sodium butyrate-induced hyperacetylation. However, acetylation itself does n ot predispose H3 to phosphorylation, nor does phosphorylation predispo se H3 to enhanced acetylation. Further, selectivity is not based on pr eferential modification of particular histone H3 subtypes. Thus, the m itogen-regulated kinase that phosphorylates histone H3 is restricted t o a small subset of nucleosomes that is especially susceptible to hype racetylation.