Nucleosomes Nucleosomes consist of DNA tightly wrapped around proteins called histones 75-90% of DNA is believed to be present in nucleosomes From faculty web page of Grant Hartzog at the University of California, Santa Cruz. (http://biomedical.ucsc.edu/Hartzog.html) The total length of double stranded DNA in the human genome is roughly two meters. In order to compactly fit this much DNA into the nucleus of a cell, the DNA is tightly wound around proteins called histones, as shown in the slide. Seventy-five to ninety percent of all genomic DNA is believed to be present in nucleosomes. © 2005 Prentice Hall Inc. / A Pearson Education Company / Upper Saddle River, New Jersey 07458

Dinucleotide patterns and nucleosome positioning Dinucleotide patterns are known to repeat in DNA wrapped around histones Researchers built predictive thermodynamic model Accurately predicted nucleosome positioning 54% of time Beats 39% accuracy predicted by chance Roughly twenty years ago, biologists found dinucleotide periodicities in the DNA sequences isolated from nucleosomes. This is schematized in the slide where a DNA sequence wrapped around a histone is meant to show the ~10 bp repeating pattern of AA/TT/TA dinucleotides. In 2006, a group of Israeli and American researchers developed a thermodynamic model that predicts the position of nucleosomes relative to a given DNA sequence. They parameterized their model using data from the DNA sequences gleaned from 199 yeast nucleosomes. The thermodynamic model was able to predict the position of nucleosomes 54% of the time, which was significantly better than the 39% prediction rate expected by chance. The yeast-based model also did reasonably well when it was used to predict the position of chicken nucleosomes. From Figure 1 in Segal E. et al. (2006) “A genomic code for nucleosome positioning” Nature 442: 772-778. © 2005 Prentice Hall Inc. / A Pearson Education Company / Upper Saddle River, New Jersey 07458

Biological implications From Figure 4 in Segal E. et al. (2006) “A genomic code for nucleosome positioning” Nature 442: 772-778. By applying the nucleosome positioning model to well characterized genomic sequences, the researchers were able to determine how nucleosome occupancy was related to the biological function associated with different DNA sequences. Occupancy was found to be highest (> 90%) in the region of the centromeres and lowest (<70%) near the telomeres and transfer RNA genes. In general, nucleosomes were significantly more common in non-functional sequences than functional sequences. The authors speculate that nucleosomes may be involved in controlling access to gene regulatory regions by competing with regulatory proteins for access to particular DNA sequences. © 2005 Prentice Hall Inc. / A Pearson Education Company / Upper Saddle River, New Jersey 07458

Caveats Accuracy of mapping could be improved DNA sequences longer than dinucleotides are likely to contribute to positioning code Chromatin remodeling factors likely to perturb nucleosome code Experiments with H1 histone protein suggest that these proteins may alter the way the nucleosome code is interpreted Despite the ambitious efforts of the nucleosome coding study, much remains to be done. The base-pair accuracy of the study could be improved, which may also yield improvements in the predictions of nucleosome positioning. In a similar vein, future studies should consider the possibility that sequences longer than dinucleotides may contribute to the positioning “code.” Also, chromatin remodeling factors, which are prevalent in eukaryotic cells, are also likely to contribute to the code. Finally, a recent study suggests that the precise pattern of expression of H1 proteins may have a dramatic effect on the arrangement of nucleosome assemblies. H1 proteins are normally involved in binding together nucleosome cores. When half of the H1 encoding genes were deleted in mouse cells, researchers found that the distance between nucleosomes decreased by 30 base pairs, suggesting that there is more to the “code” than DNA. Interestingly, the extreme reduction in H1 expression still allowed the mouse cells to survive. © 2005 Prentice Hall Inc. / A Pearson Education Company / Upper Saddle River, New Jersey 07458