Bridging chromatin structure and function over a range of experimental spatial and temporal scales by molecular modeling

Abstract

Chromatin structure, dynamics, and function are being intensely investigated by a variety of methods, including microscopy, X‐ray diffraction, nuclear magnetic resonance, biochemical crosslinking, chromosome conformation capture, and computation. The modeling helps interpret experimental data and generate configurations and mechanisms related to the three‐dimensional organization and function of the genome. Experimental contact maps, in particular, as obtained by a variety of chromosome conformation capture methods, are of increasing interest due to their implications on genome structure and regulation on many levels. In this perspective, using seven examples from our group's studies, we illustrate how molecular modeling can help interpret such experimental data. Specifically, we show how computed contact maps related to experimental systems can help interpret structures of nucleosomes, chromatin higher‐order folding, domain segregation mechanisms, gene organization, and the effect on chromatin structure of external and internal fiber parameters, such as nucleosome positioning, presence of nucleosome free regions, histone post‐translational modifications, and linker histone binding. We argue that such computations on multiple spatial and temporal scales will be increasingly important for the integration of genomic, epigenomic, and biophysical data on chromatin structure and related cellular processes. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics

Biomolecular modeling thrives in the age of technology

“…Finally, to study DNA complexed with proteins, such as in the context of chromatin fibers, multiscale approaches are essential, as recently reviewed 123,124 . These approaches derive the chromatin model from the atomistic DNA, nucleosomes and linker histones.…”

“…These approaches derive the chromatin model from the atomistic DNA, nucleosomes and linker histones. Successful models by the groups of the late Langowski 41 , Wedemann 125 , Nordenskiöld 126 , Olson 127 , Spakowitz 128 , de Pablo 129 and ours 40,123 have been applied to understand the mechanisms that regulate chromatin compaction and function. For example, our recent three-dimensional folding of the HOXC gene cluster (~55 kbp) at nucleosome resolution by mesoscale modeling 130 revealed how epigenetic factors act together to regulate chromatin folding (Fig.…”

The Multiscale Future of RNA Modeling

“…In particular, multiscale modeling combines multiple approaches by studying the same system at different levels of resolution (e.g., atomistic and residue-level) and integrating the results. Such approaches have been successfully used in modeling variety of systems such as actin and chromatin ( 6 , 7 ). The new work from Shi-Jie Chen’s group, “Modeling loop composition and ion concentration effects in RNA hairpin folding stability” ( 8 ), published in the current issue of the Biophysical Journal , shows a promising method to use multiscale models for studying the conformational folding landscape of RNA molecules.…”

Genome Dashboards: Framework and Examples

“…Super-resolution microscopy (11,12) provides optical visualization of three-dimensional (3D) structures at nanometer-scale resolution, and electron microscopy (13), NMR (14), and x-ray crystallography (15) provide ångström-scale resolution of individual nucleosomes and nucleosome arrays. Strategies for modeling chromatin structure are rapidly maturing (16)(17)(18)(19). The desire to merge computational and experimental approaches is recognized (20,21), but a significant challenge in chromatin structural biology is unifying these diverse data sets to advance our understanding of structure-function relationships and to validate genomic mechanisms of action.…”