Regulatory SNPs and their widespread effects on the transcriptome.

Currently, it is generally accepted that the cis-acting effects of noncoding variants on gene expression are a major factor for phenotypic variation in complex traits and disease susceptibility. Meanwhile, the protein products of many target genes for the identified cis-regulatory variants (rSNPs) are regulatory molecules themselves (transcription factors, effectors, components of signal transduction pathways, etc.), which implies dramatic downstream effects of these variations on complex gene networks. Here, we brief the results of recent most comprehensive studies on the role of rSNPs in transcriptional regulation across the genome.

Possible link between the synthesis of GR alpha isoforms and eIF2 alpha phosphorylation state.

Glucocorticoid hormones regulate numerous physiological processes and are widely used in the treatment of inflammation, autoimmune disease and cancer. Glucocorticoid receptor (GR) - a transcription factor, derived from a single gene, is responsible for the diverse actions of glucocorticoids. It was shown that GR gene gives rise a variety of mRNA species that produces several protein isoforms, among them GRα is the most abundant. In addition, GRα N-end-truncated protein isoforms (A, B, C, D) are generated by translational mechanisms. As it was found that the ratio between the translational isoforms amounts varied in different tissues and cell lines and distinct isoforms could control transcription of different sets of genes, molecular mechanisms underlining the synthesis of translational GRα isoforms are of great interest. It was considered that GRα isoform A is translated by a conventional linear scanning, isoform B is translated by leaky scanning, isoform C is translated by leaky scanning and ribosomal shunt whereas translation of isoform D occurs through ribosomal shunt only. Since the sequence organization of GRα mRNA strongly resembles the cases of ATF4 or ATF5, the well-known examples of reinitiation-dependent synthesis of functional isoforms, we hypothesize that translation of isoform C could be controlled by reinitiation mechanism also. If this assumption is correct, the ratio between GRα N-end isoforms could depend on the eIF2α phosphorylation state that could provide an additional connection between the GR and cellular stresses. We believe that this hypothesis could be of interest to plan more robust experiments or for better interpretation of available data.

Structural variants of glucocorticoid receptor binding sites and different versions of positive glucocorticoid responsive elements: Analysis of GR-TRRD database.

The GR-TRRD section of the TRRD database contains the presently largest sample of published nucleotide sequences with experimentally confirmed binding to the glucocorticoid hormone receptor (GR). This sample comprises 160 glucocorticoid receptor binding sites (GRbs) from 77 vertebrate glucocorticoid-regulated genes. Analysis of this sample has demonstrated that the structure of only half GRbs (54%) corresponds to the generally accepted organization of glucocorticoid response element (GRE) as an inverted repeat of the TGTTCT hexanucleotide. As many as 40% of GRbs contain only the hexanucleotide, and the majority of such "half-sites" belong to the glucocorticoid-inducible genes. An expansion of the sample allowed the consensus of GRbs organized as an inverted repeat to be determined more precisely. Several possible mechanisms underlying the role of the noncanonical receptor binding sites (hexanucleotide half-sites) in the glucocorticoid induction are proposed based on analysis of the literature data.

Combined experimental and computational approaches to study the regulatory elements in eukaryotic genes.

The recognition of transcription factor binding sites (TFBSs) is the first step on the way to deciphering the DNA regulatory code. There is a large variety of experimental approaches providing information on TFBS location in genomic sequences. Many computational approaches to TFBS recognition based on the experimental data obtained are available, each having its own advantages and shortcomings. This article provides short review of approaches to computational recognition of TFBS in genomic sequences and methods of experimental verification of predicted sites. We also present a case study of the interplay between experimental and theoretical approaches to the successful prediction of Steroidogenic Factor 1 (SF1).