Abstract
Action across long distances on chromatin is a hallmark of eukaryotic transcriptional regulation. Although chromatin structure per se can support long-range interactions, the mechanisms of efficient communication between widely spaced DNA modules in chromatin remain a mystery. The molecular simulations described herein suggest that transient binary internucleosomal interactions can mediate distant communication in chromatin. Electrostatic interactions between the N-terminal tails of the core histones and DNA enhance the computed probability of juxtaposition of sites that lie far apart along the DNA sequence. Experimental analysis of the rates of communication in chromatin constructs confirms that long-distance communication occurs efficiently and independently of distance on tail-containing, but not on tailless, chromatin. Taken together, our data suggest that internucleosomal interactions involving the histone tails are essential for highly efficient, long-range communication between regulatory elements and their targets in eukaryotic genomes.
Highlights
Gene expression is regulated by DNA elements that often lie far apart along genomic sequences
We introduced a discrete variable for each bead, which indicates whether the flexible histone tails are available for interaction with other beads
Our composite findings show that internucleosomal interactions involving the histone tails can account for long-distance regulatory communication along chromatin
Summary
Gene expression is regulated by DNA elements that often lie far apart along genomic sequences. Most eukaryotic genes are regulated by short DNA sequences called transcriptional enhancers that, after binding of proteins, can activate transcription over distances up to hundreds of kb The action of these enhancers involves the direct association of the proteins bound at the enhancer site and at its target (promoter) site, with accompanying formation of a large loop of the intervening chromatin-covered DNA (6 – 8). Both kinetic and equilibrium aspects of enhancerpromoter communication over long distances on histone-free DNA have been extensively investigated (3, 9 –12), the mechanisms of communication in chromatin remain poorly understood. Molecular simulations [16, 17] focused on a few of
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