Large-scale chromatin unfolding and remodeling induced by VP16 acidic activation domain

Analysis of the relationship between transcriptional activators and chromat in organization has focused largely on lower levels of chromatin structure. Here we describe striking remodeling of large-scale chromatin structure in duced by a strong transcriptional activator. A VP16-lac repressor fusion pr otein targeted the VP16 acidic activation domain to chromosome regions cont aining lac operator repeats. Targeting was accompanied by increased transcr iption, localized histone hyperacetylation, and recruitment of at least thr ee different histone acetyltransferases. Observed effects on large-scale ch romatin structure included unfolding of a 90-Mbp heterochromatic chromosome arm into an extended 25-40-mu m chromonema fiber, remodeling of this fiber into a novel subnuclear domain, and propagation of large-scale chromatin u nfolding over hundreds of kilobase pairs. These changes in large-scale chro matin structure occurred even with inhibition of ongoing transcription by a lpha-amanitin. Our results suggest a functional link between recruitment of the transcriptional machinery and changes in large-scale chromatin structu re. Based on the observed long-range propagation of changes in large-scale chromatin structure, we suggest a possible rationale for the observed clust ering of housekeeping genes within Mbp-sized chromosome bands.