Background The analysis of gene promoters is essential to understand the

Background The analysis of gene promoters is essential to understand the mechanisms of transcriptional regulation required under the effects of physiological processes, nutritional intake or pathologies. combinations of specific regulatory elements. These models were screened using the full human genome and databases of promoter sequences from human and several other mammalian species. For each of transcriptionally regulated genesa set of co-regulated genes was identified and their over-expression was verified in microarray databases. Conclusions Most of the identified genes encode proteins with a cellular function and specificity in agreement with those of the corresponding ANT isoform. Our study shows that the tissue specific gene expression is mainly driven by promoter regulatory sequences located up to about a thousand base pairs upstream the transcription start site. Moreover, this computational strategy on the study of regulatory pathways should provide, along with transcriptomics and metabolomics, data to construct cellular metabolic networks. genes is an interesting example of multi-isoform gene regulation. The metabolic and physiological consequences of these molecular regulatory mechanisms play a major role in the evolution of cellular metabolic pathways. Each of the four isoforms is known to play a specific role in cellular bioenergetics: ANT1 (SLC25A4) provides mitochondrial ATP for heart and skeletal muscle contraction [5]. The kinetic properties of this ANT1 isoform allow the rapid and massive mitochondrial ATP export required for muscular contraction. The second isoform, ANT2 (SLC25A5), is usually weakly or not at all expressed in human tissues and maintains the intra-mitochondrial functions under glycolytic conditions required in proliferative cells [6,7]. ANT2 is known to have a function opposite to that of ANT1 by transporting glycolytic ATP toward the mitochondrial matrix [5]. We identified a specific regulatory sequence in the promoter region of the human gene: the GRBOX element (Glycolysis Regulated Box) upstream of the TSS (transcription start site) [8]. ANT3 (SLC25A6) is the constitutively expressed ubiquitous isoform that is integrated into the mitochondrial membrane when no other isoform is produced [5]. In rodents, the gene was lost during evolution. It is possible that, unlike humans, rodent physiology does not require two isoforms with different kinetics (ANT1 and ANT3). This assumption would be supported by the disappearance, in the rodents, of the OXBOX regulatory element from the promoter [9], which would determine the muscle specific expression of this isoform. The last isoform, ANT4 (SLC25A31), was recently identified in humans, and is expressed mainly in the testicle [10]. This isoform appears in mammals and is essential during spermatogenesis [11]. Its peptide sequence is very comparable (66-68% of identity) to that of the other ANT 21019-30-7 IC50 isoforms. The main characteristic of the ANT4 isoform is the presence of additional peptides, specifically the N- (13 amino acids) and C- (8 amino acids) terminal sequences, which Rabbit polyclonal to PHC2 the other three isoforms lack. The proposed hypothesis 21019-30-7 IC50 for the role of this isoform is usually that it compensates for the loss of the gene function (encoded by the X chromosome) during male meiosis [11]. 21019-30-7 IC50 A recent computational analysis enabled us to propose a specific role for the ANT4 isoform in spermatozoid bioenergetics [2]. We pursued and developed this computational analysis to compare the mechanisms of transcriptional regulation of the four ANT isoforms through analysis of nucleotide sequences upstream of the supposed TSS. The nucleotide sequences of these promoter regions from several mammalian species were compared to follow the phylogeny of specific sequences of transcriptional regulation. Promoter sequences preserved throughout evolution might be 21019-30-7 IC50 of major importance to the survival of the organism [12]. This study is based on a combination of software and databases including those available on-line, such as Genomatix [13] and EnsEMBL [14], GeneProm from our laboratory. This analysis led to interesting conclusions linking promoter structure and co-regulation of a set of genes. Results An outline of 21019-30-7 IC50 the bioinformatics pipeline.

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