Communication between distantly spaced genomic regions is one of the key features of gene regulation in eukaryotes. Chromatin per se can stimulate efficient enhancer-promoter communication (EPC); however, the role of chromatin structure and dynamics in this process remains poorly understood. Here we show that nucleosome spacing and the presence of nucleosome-free DNA regions can modulate chromatin structure/dynamics and, in turn, affect the rate of EPC in vitro and in silico. Increasing the length of internucleosomal linker DNA from 25 to 60 bp results in more efficient EPC. The presence of longer nucleosome-free DNA regions can positively or negatively affect the rate of EPC, depending upon the length and location of the DNA region within the chromatin fiber. Thus the presence of histone-free DNA regions can differentially affect the efficiency of EPC, suggesting that gene regulation over a distance could be modulated by changes in the length of internucleosomal DNA spacers.

One of the critical unanswered questions in genome biophysics is how the primary sequence of DNA bases influences the global properties of very-long-chain molecules. The local sequence-dependent features of DNA found in high-resolution structures introduce irregularities in the disposition of adjacent residues that facilitate the specific binding of proteins and modulate the global folding and interactions of double helices with hundreds of basepairs. These features also determine the positions of nucleosomes on DNA and the lengths of the interspersed DNA linkers. Like the patterns of basepair association within DNA, the arrangements of nucleosomes in chromatin modulate the properties of longer polymers. The intrachromosomal loops detected in genomic studies contain hundreds of nucleosomes, and given that the simulated configurations of chromatin depend on the lengths of linker DNA, the formation of these loops may reflect sequence-dependent information encoded within the positioning of the nucleosomes. With knowledge of the positions of nucleosomes on a given genome, methods are now at hand to estimate the looping propensities of chromatin in terms of the spacing of nucleosomes and to make a direct connection between the DNA base sequence and larger-scale chromatin folding.Despite the astonishing amount of information now known about the sequential makeup and spatial organization of genomic DNA, there is much to learn about how the vast numbers of basepairs in these systems contribute to the three-dimensional architectures and workings of long, spatially constrained, double-helical molecules. New biochemical and imaging methodologies, such as proximity-based ligation and fluorescence in situ hybridization (1-3), have shed light on the large-scale organization of genomic DNA, enabling investigators to pinpoint DNA elements in close spatial proximity and follow the course of these associations during cellular processes. The resulting measurements have motivated the study of long genomes in terms of simple polymer models (4,5), which have in turn illuminated the physical nature of the contacted elements and pointed to mechanisms potentially governing genome architecture and dynamics. Although these models are appropriate for the very large scale of the experimental data, they rest on the assumption that the chemical makeup of DNA does not matter, and thus provide no link between the primary sequence of bases and the tertiary structures and interactions of genomic folds.At the other extreme of chain length, the detailed molecular structures of DNA with only tens of basepairs point to various sequence-dependent spatial and energetic codes underlying the three-dimensional organization of the double helix and its susceptibility to interactions with proteins and other molecules (6). The structural data also include more than 100 crystallographic examples of the tight, superhelical wrapping of~150 DNA basepairs (bp) around the core of the histone proteins in the nucleosome core particle, the fundamental packagi...

Enhancers are regulatory DNA sequences that can activate transcription over large distances. Recent studies have revealed the widespread role of distant activation in eukaryotic gene regulation and in the development of various human diseases, including cancer. Here we review recent progress in the field, focusing on new experimental and computational approaches that quantify the role of chromatin structure and dynamics during enhancer-promoter interactions in vitro and in vivo.

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The DNA of higher organisms associates with histone proteins to organize into an array of nucleosomes. The nucleosome, however, is not one monolithic structure, but rather, refers to an ensemble of assemblies that vary in the chemical modifications present, histone composition, and surrounding DNA sequence. Here, we connect computation with experimental efforts to reveal the effects of acetylation on the H4 histone tail, the impact of a centromere-specific variant on histone assembly structure and dynamics, and the influence of nucleotide sequence on nucleosome breathing. We discover increasing levels of acetylation introduce greater transient order to the H4 histone tail with the mono-acetylation of lysine 16 causing specific structural effects; replacing histone H3 with centromere-specific CENP-A confers enhanced flexibility to dimers and entire nucleosomes, but, interestingly, more rigidity to tetramers; and lastly, that DNA sequences with greater CG content form more stable nucleosomes, undergoing fewer events in which the outer stretches of DNA spontaneously detach and reattach to the histone core.