Previous studies indicate that eukaryotic promoters display a stereotypical chromatin landscape characterized by a well-positioned +1 nucleosome near the transcription start site and an upstream -1 nucleosome that together demarcate a nucleosome-free (or -depleted) region. Here we present evidence that there are two distinct types of promoters distinguished by the resistance of the -1 nucleosome to micrococcal nuclease digestion. These different architectures are characterized by two sequence motifs that are broadly deployed at one set of promoters where a nuclease-sensitive ("fragile") nucleosome forms, but concentrated in a narrower, nucleosome-free region at all other promoters. The RSC nucleosome remodeler acts through the motifs to establish stable +1 and -1 nucleosome positions, while binding of a small set of general regulatory (pioneer) factors at fragile nucleosome promoters plays a key role in their destabilization. We propose that the fragile nucleosome promoter architecture is adapted for regulation of highly expressed, growth-related genes.

Accessible chromatin is important for RNA polymerase II recruitment and transcription initiation at eukaryotic promoters. We investigated the mechanistic links between promoter DNA sequence, nucleosome positioning, and transcription. Our results indicate that positioning of the transcription start site-associated +1 nucleosome in yeast is critical for efficient TBP binding and is driven by two key factors, the essential chromatin remodeler RSC and a small set of ubiquitous general regulatory factors (GRFs). Our findings indicate that the strength and directionality of RSC action on promoter nucleosomes depends on the arrangement and proximity of two specific DNA motifs. This, together with the effect on nucleosome position observed in double depletion experiments, suggests that, despite their widespread co-localization, RSC and GRFs predominantly act through independent signals to generate accessible chromatin. Our results provide mechanistic insight into how the promoter DNA sequence instructs trans-acting factors to control nucleosome architecture and stimulate transcription initiation.

a b s t r a c tInherently complex problems from many scientific disciplines require a multiscale modeling approach. Yet its practical contents remain unclear and inconsistent. Moreover, multiscale models can be very computationally expensive, and may have potential to be executed on distributed infrastructure. In this paper we propose firm foundations for multiscale modeling and distributed multiscale computing. Useful interaction patterns of multiscale models are made predictable with a submodel execution loop (SEL), four coupling templates, and coupling topology properties. We enhance a high-level and well-defined Multiscale Modeling Language (MML) that describes and specifies multiscale models and their computational architecture in a modular way. The architecture is analyzed using directed acyclic task graphs, facilitating validity checking, scheduling distributed computing resources, estimating computational costs, and predicting deadlocks. Distributed execution using the multiscale coupling library and environment (MUSCLE) is outlined. The methodology is applied to two selected applications in nanotechnology and biophysics, showing its capabilities.

Advection-diffusion processes can be simulated by the Lattice Boltzmann method. Two formulations have been proposed in the literature. We show that they are not fully correct (only first order accurate). A new formulation is proposed, which is shown to produce better results, both from the point of view of the Chapman-Enskog expansion or when comparing simulations with an exact time-dependent solution of the advection-diffusion equation.

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