Book of Abstracts: Albany 2009
June 16-20 2009
© Adenine Press (2008)
Distinct Modes of Regulation by Chromatin Encoded through Nucleosome Positioning Signals
The detailed positions of nucleosomes profoundly impact gene regulation and are partly encoded by the genomic DNA sequence. However, less is known about the functional consequences of this encoding.
We first address this question using a genome-wide map of nucleosomes in the yeast S. cerevisiae that we sequenced in their entirety. Utilizing the high resolution of our map, we refine our understanding of how nucleosome organizations are encoded by the DNA sequence, and demonstrate that the genomic sequence is highly predictive of the in vivo nucleosome organization, even across new nucleosome-bound sequences that we isolated from fly and human. We find that Poly(dA:dT) tracts are an important component of these nucleosome positioning signals, and that their nucleosome-disfavoring action results in large nucleosome-depletion over them and over their flanking regions, and enhances the accessibility of transcription factors to their cognate sites. These results suggest that the yeast genome may utilize these nucleosome positioning signals to regulate gene expression with different transcriptional noise and activation kinetics, and DNA replication with different origin efficiency. These distinct functions may be achieved by encoding both relatively closed (nucleosome-covered) chromatin organizations over some factor binding sites, where factors must compete with nucleosomes for DNA access, and relatively open (nucleosome-depleted) organizations over other factor sites, where factors bind without competition.
In further work we have investigated the DNA-encoded nucleosome organization of promoters in the two related yeast species S. cerevisiae and C. albicans. For that we have measured in-vivo nucleosome positions in both species, and further have measured the in-vitro nucleosome positions of purified histone octamers assembled on purified genomic DNA from both species. The latter is thus the direct measurement of the DNA sequence contribution to the nucleosome positioning and is independent of transcription and replication states, and of the action and binding of chromatin remodelers and transcription factors. We first show that most changes in the nucleosome organization of promoters between these species (measured in-vivo) are attributed to changes in the DNA sequence (measured in-vitro and predicted by our model). We then show a global relationship between transcriptional programs of genes (based on microarray expression profiles of genes along different conditions and cellular states) and the DNA-encoded nucleosome organizations of their promoters that is remarkably conserved across these yeast species, even in the presence of expression divergence. Growth related genes that are by 'default' on, tend to have the open DNA-encoded nucleosome organization for their promoters, which presumably facilitates for them a default accessible promoter state. Inducible genes (condition or cellular state specific genes) that are by default off tend to have the closed DNA-encoded nucleosome organization, which presumably facilitates for them a default inaccessible promoter state.
In summary, in these work we report on progress in understanding the way in which nucleosome organization is encoded in the DNA, and in identifying functional consequences of the DNA-encoded nucleosome organization in both replication and transcription regulation.
1Dept. of Computer Science and Applied Mathematics