Incorporating Nucleosomes into Thermodynamic Models of Transcription Regulation

Abstract

Transcriptional control is central to many cellular processes and consequently, much effort has been devoted to understanding its underlying mechanisms. The organization of nucleosomes along promoter regions is important for this process, since most transcription factors cannot bind nucleosomal sequences, and thus compete with nucleosomes for DNA access. This competition is governed by the relative concentrations of nucleosomes and transcription factors and by their respective sequence binding preferences. However, despite its importance, a mechanistic understanding of the quantitative effects that the competition between nucleosomes and factors has on transcription is still missing. Here we employ a thermodynamic framework based on fundamental principles of statistical mechanics to theoretically explore the effect that different nucleosome organizations along promoters have on the activation dynamics of promoters in response to varying concentrations of the regulating factors. We show that even simple landscapes of nucleosome organization reproduce experimental results regarding the effect of nucleosomes as general repressors and as generators of obligate binding cooperativity between factors. Our modeling framework also allows us to characterize the effects that various sequence elements of promoters have on the induction threshold and on the shape of the promoter activation curves. Finally, we show that using only sequence preferences for nucleosomes and transcription factors, our model can also predict expression of real promoter sequences, thereby underscoring the importance of the interplay between nucleosomes and factors in determining expression kinetics. This paper is accompanied by supplementary information.