Fitness landscape for nucleosome positioning

Abstract

Histone-DNA complexes, so-called nucleosomes, are the building blocks of DNA packaging in eukaryotic cells. The histone-binding affinity of a local DNA segment depends on its elastic properties and determines its accessibility within the nucleus, which plays an important role in the regulation of gene expression. Here, we derive a fitness landscape for intergenic DNA segments in yeast as a function of two molecular phenotypes: their elasticity-dependent histone affinity and their coverage with transcription factor binding sites. This landscape reveals substantial selection against nucleosome formation over a wide range of both phenotypes. We use it as the core component of a quantitative evolutionary model for intergenic DNA segments. This model consistently predicts the observed diversity of histone affinities within wild Saccharomyces paradoxus populations, as well as the affinity divergence between neighboring Saccharomyces species. Our analysis establishes histone binding and transcription factor binding as two separable modes of sequence evolution, each of which is a direct target of natural selection.biophysics | nucleosome-depleted regions | evolution of regulation | quantitative traits | inference of selection T he positional organization of nucleosomes in eukaryotic cells is of key importance for the overall chromatin structure and, thus, for the regulation of gene expression (1-3). Nucleosomes form through binding of a histone octamer to a DNA sequence segment of average length 146 base pairs (bp), which wraps around the protein complex (4). Histone-bound DNA segments are interspersed with unbound "linker" segments. Particularly prominent features of this pattern are so-called nucleosome-depleted regions (NDRs). These are extended troughs in occupancy at least ∼100 bp long, primarily located in intergenic DNA. Changes in nucleosome positioning affect the accessibility of local DNA segments for binding interactions with transcription factors and lead to observable changes of gene expression in yeast (3,5).Explaining two correlated molecular functions-histone binding and transcriptional regulation-in the same sequence segment may be seen as a chicken-and-egg problem (6-9). Is transcription factor binding the primary function, which displaces nucleosomes to sequence segments in which transcription is neutral or deleterious? Or, conversely, does nucleosome positioning constrain transcriptional interactions? Here, we address this problem by a quantitative evolutionary analysis of yeast genomes. We infer a fitness landscape for intergenic sequence segments that measures selection on their regulatory interactions and on local nucleosome formation. We capture these functions by two molecular phenotypes, the regulatory binding site content and the histone binding affinity, which reflect distinct biophysical characteristics of a DNA segment. The fitness landscape resulting from our analysis shows substantial selection acting jointly on transcriptional interactions and on nucleosome formation. Specifically, we fi...

Increasing Nucleosome Occupancy Is Correlated with an Increasing Mutation Rate so Long as DNA Repair Machinery Is Intact

“…Overall, the data demonstrates an increase in the mutation rate for nucleosome favoring DNA nucleotides as previous work by others has shown that the nucleosome core particle is enriched for Gs and Cs and relatively depleted of As and Ts[ 32 ]. This is consistent with recent work in yeast that observed selection against nucleosome favoring sequences in NDR and nucleosome disfavoring sequences in nucleosomal DNA[ 33 ]. The greatest overall increase was observed in the rate of change from A→G.…”

Coupling between Sequence-Mediated Nucleosome Organization and Genome Evolution

“…The transcriptional changes during cell life processes such as differentiation, reprogramming, stress or even aging are associated with changes in nucleosome occupancy [82][83][84][85]. Modifying the nucleosome organization at some loci is thus expected to have either a positive or a negative impact on the fitness of an individual [86]. As nucleosome positions are at least partially sequence-encoded (Section 2), this strongly suggests that natural selection on DNA sequence could have an impact on the nucleosomal positioning.…”

A thousand empirical adaptive landscapes and their navigability

“…Supplementary Figs. [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. While experiments are required to determine which parameters and assumptions best reflect the true binding affinity landscapes, the following in vivo analyses suggest that the baseline parameter combination studied here provides meaningful information about TF binding in both yeast and mouse, two highly diverged eukaryotic species.…”

“…We describe the mapping of DNA sequence to binding affinity as an adaptive landscape, where we can study selection for TF binding. This is a common approach for exploring the evolution of TF binding sites [12][13][14][15][16] , other protein-DNA interactions 5,17,18 , and protein-RNA interactions 19 . In this context, adaptive evolution is an exploration of sequence space that attempts to optimize the capacity of a sequence to bind a particular TF.…”