MULTOVL: fast multiple overlaps of genomic regions.

We present the MULTOVL application suite that detects and statistically analyses multiple overlaps of genomic regions in a fast and efficient manner. The package supports the detection of multiple region intersections, unions and 'solitary' genomic regions. The significance of actually observed overlaps is estimated by comparing them with empirical null distributions generated by random shuffling of the input regions.

Intergenic Polycomb target sites are dynamically marked by non-coding transcription during lineage commitment.

Non-coding (nc) RNAs are involved both in recruitment of vertebrate Polycomb (PcG) proteins to chromatin, and in activation of PcG target genes. Here we investigate dynamic changes in the relationship between ncRNA transcription and recruitment of PcG proteins to chromatin during differentiation. Profiling of purified cell populations from different stages of a defined murine in vitro neural differentiation system shows that over 50% of regulated intergenic non-coding transcripts precisely correspond to PcG target sites.

H3K27me3 forms BLOCs over silent genes and intergenic regions and specifies a histone banding pattern on a mouse autosomal chromosome.

In mammals, genome-wide chromatin maps and immunofluorescence studies show that broad domains of repressive histone modifications are present on pericentromeric and telomeric repeats and on the inactive X chromosome. However, only a few autosomal loci such as silent Hox gene clusters have been shown to lie in broad domains of repressive histone modifications. Here we present a ChIP-chip analysis of the repressive H3K27me3 histone modification along chr 17 in mouse embryonic fibroblast cells using an algorithm named broad local enrichments (BLOCs), which allows the identification of broad regions of histone modifications.

Analyzing the performance of conformational search programs on compound databases.

We have studied the sampling performance of conformational search programs using geometric and energetic criteria. Ideally, a conformational search algorithm should identify the largest possible number of low-energy structures (energy criterion) covering the widest possible range of molecular shapes (geometric criterion). Geometric analysis consisted in comparing the distribution of conformations within the generated ensembles by multidimensional scaling and by analysing the eigenvalue structure of the pairwise coordinate covariance matrices.

SH2 binding site comparison: a new application of the SURFCOMP method.

To avoid side effects, it is often desirable to increase the specificity of a drug candidate when targeting one member of a family of related proteins, whereby one exploits small differences between the structures of the binding sites. Identification of such differences can be carried out by analyzing the distributions of physicochemical properties mapped onto molecular surfaces. Here we demonstrate that SURFCOMP, our local surface similarity detection method, is able to detect differences between the binding sites of two closely related proteins.

mRNA openers and closers: modulating AU-rich element-controlled mRNA stability by a molecular switch in mRNA secondary structure.

Approximately 3 000 genes are regulated in a time-, tissue-, and stimulus-dependent manner by degradation or stabilization of their mRNAs. The process is mediated by interaction of AU-rich elements (AREs) in the mRNA's 3'-untranslated regions with trans-acting factors. AU-rich element-controlled genes of fundamentally different functional relevance depend for their activation on one positive regulator, HuR.

SURFCOMP: a novel graph-based approach to molecular surface comparison.

Analysis of the distributions of physicochemical properties mapped onto molecular surfaces can highlight important similarities or differences between compound classes, contributing to rational drug design efforts. Here we present an approach that uses maximal common subgraph comparison and harmonic shape image matching to detect locally similar regions between two molecular surfaces augmented with properties such as the electrostatic potential or lipophilicity. The complexity of the problem is reduced by a set of filters that implement various geometric and physicochemical heuristics.

Percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus.

For treatment of skin diseases with topical drugs, penetration of the agents into the relevant layers of the skin is required. Permeation through the skin should, however, be kept to a minimum, in order to avoid the risk of systemic side effects. Here we compared the in vitro skin penetration and permeation of two novel drugs used in the therapy of atopic eczema (pimecrolimus and tacrolimus) and three representative corticosteroids (betamethasone-17-valerate, clobetasol-17-propionate, and diflucortolon-21-valerate).