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Modeling interactions between adjacent nucleosomes improves genome-wide predictions of nucleosome occupancy


Shai Lubliner1, Eran Segal1,2,†


Motivation: Understanding the mechanisms that govern nucleosome positioning over genomes in vivo is essential for unraveling the role of chromatin organization in transcriptional regulation. Until now, models for predicting genome-wide nucleosome occupancy have assumed that the DNA associations of neighboring nucleosomes on the genome are independent. We present a new model that relaxes this independence assumption by modeling interactions between adjacent nucleosomes.

Results: We show that modeling interactions between adjacent nucleosomes improves genome-wide nucleosome occupancy predictions in an in vitro system that includes only nucleosomes and purified DNA, where the resulting model has a preference for short spacings (linkers) of less than 20 bp in length between neighboring nucleosomes. Since nucleosome occupancy in vitro depends only on properties intrinsic to nucleosomes, these results suggest that the interactions we find are intrinsic to nucleosomes and do not depend on other factors, such as transcription factors and chromatin remodelers. We also show that modeling these intrinsic interactions significantly improves genome-wide predictions of nucleosome occupancy in vivo.



 

We present a new thermodynamic model for genomewide prediction of nucleosome occupancy. The new model extends a previous one by modeling interactions between adjacent nucleosomes using a function that depends on the linker length. (A) Using a model with interactions represented by a decaying exponent function (Exp) we can better explain nucleosome occupancy data than with a model that lacks interactions (No Coop). This is true for data from all of the following (B-D): (B) An in-vitro system of nucleosomes and yeast DNA. Since no other factors affect the in-vitro system, the modeled interactions are intrinsic to the association of nucleosomes and DNA. (C) yeast in-vivo. This demonstrates that the modeled interactions play a significant role in-vivo as well. (D) C. Elegans in-vivo. This shows that the interactions are universal, and not unique to yeast. (E) The linker lengths distributions produced by the above model with interactions (Exp, in blue), and by the model without interactions (No Coop, in magenta). The modeled interactions favor short linker lengths. (F) An illustration of how the modeled interactions may affect nucleosome occupancy and the linker lengths distribution. The interactions attract adjacent nucleosomes closer along the DNA strand, energetically compensating for possible shifts from otherwise favored positions (in gold, based solely on the DNA sequence). It is conceivable that such interactions may also play a role in DNA bending and hence affect higher orders of chromatin organization. (G) Since the modeled interactions are intrinsic and involve nucleosomes that are close to each other, we hypothesize that they are electrostatic interactions. These may occur between oppositely charged patches on the nucleosome cores themselves (left), or may involve the histone tails (right).

 


Correspondence should be addressed to E.S.
1 Dept. of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel.
2 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.