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Distinct Modes of Regulation by Chromatin Encoded through Nucleosome Positioning Signals


Yair Field1*, Noam Kaplan1*, Yvonne Fondufe-Mittendorf2*, Irene K. Moore2, Eilon Sharon1, Yaniv Lubling1, Jonathan Widom2†, Eran Segal1,3†


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. Here, we address this question using a genome-wide map of ~380,000 yeast nucleosomes 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. Our 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.

 

Illustration: Yeast promoters have an in-vivo average characteristic of a nucleosome depleted region. This organization is encoded in the DNA sequence by nucleosome positioning signals, that include a nucleosome favoring periodic pattern of certain dinucleotides and nucleosome disfavoring sequences such as Poly(dA:dT) tracts. However, promoters can be characterized into two extreme cases of DNA-encoded (or measured) relatively open and relatively closed chromatin organizations, which are distinct in several functional correlates such as number and organization of known TF binding sites, histone turnover rate, and transcriptional noise. Promoters with relatively closed DNA-encoded (or measured) nucleosome organizations have more TF binding sites and which are more spread over the promoter region and, in accordance with an assumed model of competition between TFs and nucleosomes for promoter occupancy, they have significantly higher histone turnover rates and significantly higher transcriptionnal noise (i.e., cell-cell expression variability).

 


1 Dept. of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel.
2 Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, 2153 Sheridan Road, Evanston, IL 60208 USA.
3 Department of. Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
* These authors contributed equally to this work.
Correspondence should be addressed to J.W. or E.S.