KIRMES: kernel-based identification of regulatory modules in euchromatic sequences

Motivation: Understanding transcriptional regulation is one of the main challenges in computational biology. An important problem is the identification of transcription factor (TF) binding sites in promoter regions of potential TF target genes. It is typically approached by position weight matrix-based motif identification algorithms using Gibbs sampling, or heuristics to extend seed oligos. Such algorithms succeed in identifying single, relatively well-conserved binding sites, but tend to fail when it comes to the identification of combinations of several degenerate binding sites, as those often found in cis-regulatory modules

Large-scale structural analysis of the core promoter in mammalian and plant genomes

DNA encodes at least two independent levels of functional information. The first level is for encoding proteins and sequence targets for DNA-binding factors, while the second one is contained in the physical and structural properties of the DNA molecule itself. Although the physical and structural properties are ultimately determined by the nucleotide sequence itself, the cell exploits these properties in a way in which the sequence itself plays no role other than to support or facilitate certain spatial structures. In this work, we focus on these structural properties, comparing them between different organisms and assessing their ability to describe the core promoter. We prove the existence of distinct types of core promoters, based on a clustering of their structural profiles. These results indicate that the structural profiles are much conserved within plants (Arabidopsis and rice) and animals (human and mouse), but differ considerably between plants and animals. Furthermore, we demonstrate that these structural profiles can be an alternative way of describing the core promoter, in addition to more classical motif or IUPAC-based approaches. Using the structural profiles as discriminatory elements to separate promoter regions from non-promoter regions, reliable models can be built to identify core-promoter regions using a strictly computational approach

Hydrophobicity patterns in protein design and differential motif finding in DNA

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Physics, 2004.Includes bibliographical references (p. 115-124).(cont.) is dictated by the solvent accessibility of structures. The distinct intrinsic tendencies of sequence and structure profiles are most pronounced at long periods, where sequence hydrophobicity fluctuates less, while solvent accessibility fluctuates more than average. Correlations between the two profiles can be interpreted as the Boltzmann weight of the solvation energy at room temperature. Chapter 4 shows that correlations in solvent accessibility along protein structures play a key role in the designability phenomenon, for both lattice and natural proteins. Without such correlations, as predicted by the Random Energy Model (REM), all structures will have almost equal values of designability. By using a toy, Ising-based model, we show that changing the correlations moves between a regime with no designability and a regime exhibiting the designability phenomenon, where a few highly designable structures emerge. Understanding how gene expression is regulated is one of the main goals of molecular cell biology. To reach this goal, the recognition and identification of DNA motifs--short patterns in biological sequences--is essential. Common examples of motifs include transcription factor binding sites in promoter regions of co-regulated genes and exonic and intronic splicing enhancers ...In the past decade, a large amount of biological data has been generated, enabling new quantitative approaches in biology. In this thesis, we focus on two biological questions by using techniques from statistical physics: hydrophobicity patterns in proteins and their impact on the designability of protein structures and regulatory motif finding in DNA sequences. Proteins fold into specific structures to perform their functions. Hydrophobicity is the main force of folding; protein sequences try to lower the ground state energy of the folded structure by burying hydrophobic monomers in the core. This results in patterns, or correlations, in the hydrophobic profiles of proteins. In this thesis, we study the designability phenomena: the vast majority of proteins adopt only a small number of distinct folded structures. In Chapter 2, we use principal component analysis to characterize the distribution of solvent accessibility profiles in an appropriate high-dimensional vector space and show that the distribution can be approximated with a Gaussian form. We also show that structures with solvent accessibility profiles dissimilar to the rest are more likely to be highly designable, offering an alternative to existing, computationally-intensive methods for identifying highly-designable structures. In Chapter 3, we extend our method to natural proteins. We use Fourier analysis to study the solvent accessibility and hydrophobicity profiles of natural proteins and show that their distribution can be approximated by a multi-variate Gaussian. The method allows us to separate the intrinsic tendencies of sequence and structure profiles from the interactions that correlate them; we conclude that the alpha-helix periodicity in sequence hydrophobicityby Mehdi Yahyanejad.Ph.D

RNA G-Quadruplexes in the model plant species Arabidopsis thaliana: prevalence and possible functional roles

Tandem stretches of guanines can associate in hydrogen-bonded arrays to form G-quadruplexes, which are stabilized by K+ ions. Using computational methods, we searched for G-Quadruplex Sequence (GQS) patterns in the model plant species Arabidopsis thaliana. We found ∼1200 GQS with a G3 repeat sequence motif, most of which are located in the intergenic region. Using a Markov modeled genome, we determined that GQS are significantly underrepresented in the genome. Additionally, we found ∼43 000 GQS with a G2 repeat sequence motif; notably, 80% of these were located in genic regions, suggesting that these sequences may fold at the RNA level. Gene Ontology functional analysis revealed that GQS are overrepresented in genes encoding proteins of certain functional categories, including enzyme activity. Conversely, GQS are underrepresented in other categories of genes, notably those for non-coding RNAs such as tRNAs and rRNAs. We also find that genes that are differentially regulated by drought are significantly more likely to contain a GQS. CD-detected K+ titrations performed on representative RNAs verified formation of quadruplexes at physiological K+ concentrations. Overall, this study indicates that GQS are present at unique locations in Arabidopsis and that folding of RNA GQS may play important roles in regulating gene expression