In vertebrates and plants, epigenetic inheritance is likely to depend on both DNA methylation and specialized domains of higher order chromatin. These mechanisms are under study at a number of well-characterized genetic loci, but the "epigenome" as a whole remains little explored. Fortunately, with rapid progress in sequencing vertebrate genomes, it should soon be practical to map numerous new chromatin domains and to investigate their genetic determinants. Along these lines, we have explored the utility of a PCR-based genome screening approach. Oligonucleosomes were fractionated by chromatin immunoprecipitation using affinity-purified polyclonal anti-acetyl lysine antibodies. A sampling strategy akin to differential display was employed, with several cycles of relaxed PCR followed by amplification under more stringent conditions. Paired arbitrary primers were used and the number of cycles minimized by incorporation of 33P-labeled deoxynucleotide triphosphates. Results from such experiments reveal a broad distribution of apparent histone acetylation states, with ratios in bound (B) vs. non-bound (NB) fractions varying from 0.2 to approximately 10 relative to bulk chromatin (the latter being set to a ratio of one by normalization of B and NB pools). Loci with low B:NB ratios, consistent with having a heterochromatin-like acetylation state, tend to reside in gene-poor regions and in some cases overlap with LINE repeats. By contrast, loci partitioning primarily into the B fraction typically occur within or close to putative gene control regions. To date, experiments have sampled 1,000-2,000 loci; as will be discussed, however, it should be feasible to increase throughput considerably. Once optimized, this approach should yield information on the extent to which chromatin structures remodel in differentiation programs or pathological states.