Interactive Chromatin Folding, Nucleosome (Mis)Positioning and Chromatin Structure

Abstract

In the absence of the myriad influences that exist in a cell nucleus, the positioning and stability of nucleosomes on a short segment of DNA are governed by the material properties of the DNA. In the simplest view sequences of DNA that are intrinsically flexible or that are intrinsically curved lead to nucleosome positioning. Nucleosome positioning is thus an intra-nucleosome based effect. In vivo or for sequences of DNA that support multiple nucleosomes, nucleosome-nucleosome interactions and extra-nucleosomal (e.g. chromatin remodeling factors) interactions must also be considered.In case of intra-nucleosomal based positioning, DNA material defects (defined as variations in flexibility or conformation) are hidden because the histones force the DNA to assume a well defined super helical fold. Except for specifically constructed sequences of DNA, chromatin structures determined by intra-nucleosome interactions are irregular because the nucleosome positions will be irregular.In case inter- or extra- nucleosomal interactions determine the nucleosome positions some DNA defects will be exposed in linker DNA regions. Exposure of the defects impacts the global structure of chromatin, e.g. a bent linker yields bent chromatin.We propose that chromatin structure is biased toward one method of positioning or the other depending on environmental conditions. Thus for a given sequence of DNA both irregular and regular structures can be obtained. Our Interactive Chromatin Modeling Web Server http://www.latech.edu/∼bishop captures these ideas. Here we present a case study of how ICM Web can be used to study the folding of the mouse mammary tumor virus promoter complex(MMTV). ICM properly predicts the locations of six positioned nucleosomes in the MMTV and shows how mispositioning reveals sequence specific material defects that bend chromatin.