A Genomic Code for Nucleosome Positioning and Chromosome Function

Eran Segal
The Weizmann Institute

Eukaryotic genomes do not exist in vivo as naked DNA molecules, but are instead highly compacted into protein-DNA complexes known as chromatin. This compaction is achieved by tightly wrapping short stretches of the DNA around cores of "histone" proteins, forming structures known as nucleosomes. This architectural motif is repeated at close intervals along the entire length of each chromosomal DNA molecule, such that ~75-90% of the genomic DNA is wrapped in nucleosomes. The nucleosome structure occludes the wrapped DNA from access by most DNA binding proteins, including DNA and RNA polymerase, regulatory, repair, and recombination complexes. Consequently, nucleosomes act as general repressors, and hence understanding the driving forces and mechanism by which nucleosomes are placed along the genome has important implications for all aspects of gene regulation and chromosome function.
In this study, we utilized a combined experimental and computational approach to discover and decode a new kind of genetic information, encoded in the genomes of all eukaryotes, that specifies the organization and positioning of nucleosomes that is intrinsic to the genomic sequence. We show that this nucleosome positioning code occurs abundantly across the entire genome and is highly conserved from yeast to human. We show both with new experiments and by comparison to published data, that this novel positioning code can, on its own, successfully predict ~50% of the entire in vivo nucleosome organization. We also prove the correctness of this code in in vitro experiments, by showing that we can successfully predict sequence changes that would increase the affinity of the nucleosome to the DNA as well as sequence changes that would decrease this affinity. Our results establish that genomes utilize this nucleosome positioning code to direct transcription factors to their appropriate binding sites in the genome, and to facilitate many other specific chromosome functions, including transcription initiation, and even remodeling of the nucleosomes themselves.