On the role of transcription in positioning nucleosomes

Nucleosome positioning is crucial for the genome's function. Though the role of DNA sequence in positioning nucleosomes is well understood, a detailed mechanistic understanding on the impact of transcription remains lacking. Using numerical simulations, we investigated the dependence of nucleosome density profiles on transcription level across multiple species. We found that the low nucleosome affinity of yeast, but not mouse, promoters contributes to the formation of phased nucleosomes arrays for inactive genes. For the active genes, a heterogeneous distribution of +1 nucleosomes, caused by a tug-of-war between two types of remodeling enzymes, is essential for reproducing their density profiles. In particular, while positioning enzymes are known to remodel the +1 nucleosome and align it toward the transcription start site (TSS), spacer enzymes that use a pair of nucleosomes as their substrate can shift the nucleosome array away from the TSS. Competition between these enzymes results in two types of nucleosome density profiles with well- and ill-positioned +1 nucleosome. Finally, we showed that Pol II assisted histone exchange, if occurring at a fast speed, can abolish the impact of remodeling enzymes. By elucidating the role of individual factors, our study reconciles the seemingly conflicting results on the overall impact of transcription in positioning nucleosomes across species. Author summary Nucleosome positioning plays a key role in the genome's function by regulating the accessibility of protein binding sites as well as higher-order chromatin organization. Though significant progress has been made towards studying the role of DNA sequence in positioning the nucleosomes, our understanding on the impact of transcription lags behind. Our study uses kinetic simulations to explore the role of DNA sequence specificity, transcription factor binding, enzyme remodeling, and Pol II elongation in positioning nucleosomes. It suggests that the differences in nucleosome density profiles observed at various transcription levels in yeast and mouse embryonic stem cells can be understood from a tug-of-war between two types of remodeling enzymes.