No abstract

Background: Gene expression is regulated by DNA elements that often lie far apart along genomic sequences. Results: Novel computations and experiments provide new structural insights into long-range communication on chromatin. Conclusion: Efficient long-range association of transcriptional elements requires intact tails on the core histones. Significance: The understanding of action-at-a-distance in three dimensions helps to connect nucleosome structure/positioning to chromatin dynamics and gene regulation.

Maintenance of alternative chromatin states through cell divisions pose some fundamental constraints on the dynamics of histone modifications. In this paper, we study the systems biology of epigenetic inheritance by defining and analyzing general classes of mathematical models. We discuss how the number of modification states involved plays an essential role in the stability of epigenetic states. In addition, DNA duplication and the consequent dilution of marked histones act as a large perturbation for a stable state of histone modifications. The requirement that this large perturbation falls into the basin of attraction of the original state sometimes leads to additional constraints on effective models. Two such models, inspired by two different biological systems, are compared in their fulfilling the requirements of multistability and of recovery after DNA duplication. We conclude that in the presence of multiple histone modifications that characterize alternative epigenetic stable states, these requirements are more easily fulfilled.

We propose a model of a heterogeneous glass-forming liquid and compute the low-temperature behavior of a tagged molecule moving within it. This model exhibits stretched-exponential decay of the wave-number-dependent, self-intermediate scattering function in the limit of long times. At temperatures close to the glass transition, where the heterogeneities are much larger in extent than the molecular spacing, the time dependence of the scattering function crosses over from stretched-exponential decay with an index b=1/2 at large wave numbers to normal, diffusive behavior with b=1 at small wave numbers. There is a clear separation between early-stage, cage-breaking beta relaxation and late-stage alpha relaxation. The spatial representation of the scattering function exhibits an anomalously broad exponential (non-Gaussian) tail for sufficiently large values of the molecular displacement at all finite times.

Long-distance regulatory interactions between enhancers and their target genes are commonplace in higher eukaryotes. Interposed boundaries or insulators are able to block these long-distance regulatory interactions. The mechanistic basis for insulator activity and how it relates to enhancer action-at-a-distance remains unclear. Here we explore the idea that topological loops could simultaneously account for regulatory interactions of distal enhancers and the insulating activity of boundary elements. We show that while loop formation is not in itself sufficient to explain action at a distance, incorporating transient nonspecific and moderate attractive interactions between the chromatin fibers strongly enhances long-distance regulatory interactions and is sufficient to generate a euchromatin-like state. Under these same conditions, the subdivision of the loop into two topologically independent loops by insulators inhibits interdomain interactions. The underlying cause of this effect is a suppression of crossings in the contact map at intermediate distances. Thus our model simultaneously accounts for regulatory interactions at a distance and the insulator activity of boundary elements. This unified model of the regulatory roles of chromatin loops makes several testable predictions that could be confronted with in vitro experiments, as well as genomic chromatin conformation capture and fluorescent microscopic approaches. chromatin-polymer model | enhancer-promoter | long-range gene regulation U nlike most known cases of transcriptional regulation in prokaryotes and lower eukaryotes, metazoan genes are often regulated by enhancers placed tens to hundreds of kilobases away from the promoter (1-4). Facilitating mechanisms are necessary for such long-range enhancer action, as we shall explain below. Widespread distant regulation also requires additional mechanisms to ensure specificity. Enhancer-blocking DNA sequences, known as boundaries or insulators, define chromatin domains within which enhancer action is limited (5-11). While it is known that insulator elements bind to particular proteins (12) how these protein complexes manage to block enhancer action across domains remains controversial.Several different models for long-range enhancer-promoter communication have been proposed, for review see refs. 5, 10. One model hypothesizes a tracking mechanism that involves the processive movement of regulatory machines launched from the enhancer towards the promoter. Another model hypothesizes that transcriptional up-regulation requires direct physical contact between proteins assembled at the enhancer and the transcriptional apparatus at promoter. This process necessarily leads to looping out the intervening chromatin. Looping model has received significant support in the context of the control of the betaglobin locus by the LCR (13,14). For each of these models of enhancer-promoter communication, one needs a corresponding mechanism of action for insulators (9, 10, 15, 16). For the tracking model, insulators are assumed to...