Statistical assessment of the global regulatory role of histone acetylation in Saccharomyces cerevisiae

We analyzed recent genomewide histone acetylation data using a few complementary statistical models and tested the validity of a cumulative model in approximating the global regulatory effect of histone acetylation. Confounding effects due to transcription factor binding sequence information were estimated by using two independent motif-based algorithms followed by a variable selection method. We found that the sequence information has a significant role in regulating transcription, and we also found a clear additional histone acetylation effect. Our model fits well with observed genome-wide data. Strikingly, including more complicated combinatorial effects does not improve the model's performance. Through a statistical analysis of conditional independence, we found that H4 acetylation may not have significant direct impact on global gene expression.Decoding the combinatorial complexity of histone modification requires not only new data but also new methods to analyze the data. Our statistical analysis confirms that histone acetylation has a significant effect on gene transcription rates in addition to that attributable to upstream sequence motifs. Our analysis also suggests that a cumulative effect model for global histone acetylation is justified, although a more complex histone code may be important at specific gene loci. We also found that the regulatory roles among different histone acetylation sites have important differences.Gene activities in eukaryotic cells are concertedly regulated by transcription factors and chromatin structure. The basic repeating unit of chromatin is the nucleosome, an octamer containing two copies each of four core histone proteins. Recent microarray based studies [1-8] have begun to uncover the global regulatory role of nucleosome positioning and modifications. While nucleosome occupancy in promoter regions typically occludes transcription factor binding, thereby repressing global gene expression [1-8], the role of histone modificat