The phosphorylation status of a cyclic AMP-responsive activator is modulated via a chromatin-dependent mechanism

Cyclic AMP (cAMP) stimulates the expression of numerous genes via the prote in kinase A (PKA)-mediated phosphorylation of CREB at Ser133, Ser133 phosph orylation, in turn, promotes recruitment of the coactivator CREB binding pr otein and its paralog p300, histone acetyltransferases (HATs) that have bee n proposed to mediate target gene activation, in part, by destabilizing pro moter bound nucleosomes and thereby allowing assembly of the transcriptiona l apparatus. Here we show that although histone deacetylase (HDAC) inhibito rs potentiate target gene activation via cAMP, they do not stimulate transc ription over the early burst phase, during which CREB phosphorylation and C BP/p300 recruitment are maximal, Rather, HDAC inhibitors augment CREB activ ity during the late attenuation phase by prolonging CREB phosphorylation on chromosomal but, remarkably, not on extrachromosomal templates, In reconst itution studies, assembly of periodic nucleosomal arrays on a cAMP-responsi ve promoter template potently inhibited CREB phosphorylation by PKA, and ac etylation of these template-bound nucleosomes by p300 partially rescued CRE B phosphorylation by PKA, Our results suggest a novel regulatory mechanism by which cellular HATs and HDACs modulate the phosphorylation status of nuc lear activators in response to cellular signals.