Biomedical subjects

Michal Dabrowski

Publications and source records attributed to Michal Dabrowski.

7 recordsLinked to original sources

PubMed2006

Prediction of a key role of motifs binding E2F and NR2F in down-regulation of numerous genes during the development of the mouse hippocampus.

BACKGROUND: We previously demonstrated that gene expression profiles during neuronal differentiation in vitro and hippocampal development in vivo were very similar, due to a conservation of the important second singular value decomposition (SVD) mode (Mode 2) of expression. The conservation of Mode 2 suggests that it reflects a regulatory mechanism conserved between the two systems. In either dataset, the expression vectors of all the genes form two large clusters that differ in the sign of the contribution of Mode 2, which for the majority of them reflects the difference between down- or up-regulation. RESULTS: In the current work, we used a novel approach of analyzing cis-regulation of gene expression in a subspace of a single SVD mode of temporal expression profiles. In the putative upstream regulatory sequences identified by mouse-human homology for all the genes represented in either dataset, we searched for simple features (motifs and pairs of motifs) associated with either sign of the loading of Mode 2. Using a cross-system training-test set approach, we identified E2F binding sites as predictors of down-regulation of gene expression during hippocampal development. NR2F binding sites, for the transcription factors Nr2f/COUP and Hnf4, and also NR2F_SP1 pairs of binding sites, were predictors of down-regulation of expression both during hippocampal development and neuronal differentiation. Analysis of another dataset, from gene profiling of myoblast differentiation in vitro, shows that the conservation of Mode 2 extends to the differentiation of mesenchymal cells. This permitted the identification of two more pairs of motifs, one of which included the CDE/CHR tandem element, as features associated with down-regulation both in the differentiating myoblasts and in the developing hippocampus. Of the features we identified, the E2F and CDE/CHR motifs may be associated with the cycling progenitor cell status, while NR2F may be related to the entry into differentiation along the neuronal pathway. CONCLUSION: Our results constitute the first prediction of an expression pattern from the genomic sequence for the developing mammalian brain, and demonstrate a potential for the analysis of gene regulation in a subspace of a single SVD mode of expression.

Amino Acid Motifs↗

PubMed2006

Epileptogenesis-related genes revisited.

The main goal of this study was to identify common features in the molecular response to epileptogenic stimuli across different animal models of epileptogenesis. Therefore, we compared the currently available literature on the global analysis of gene expression following epileptogenic insult to search for (i) highly represented functional gene classes (GO terms) within data sets, and (ii) individual genes that appear in several data sets, and therefore, might be of particular importance for the development of epilepsy due to different etiologies. We focused on two well-described models of brain insult that induce the development of spontaneous seizures in experimental animals: status epilepticus and traumatic brain injury. Additionally, a few papers describing gene expression in rat and human epileptic tissue were included for comparison. Our analysis revealed that epileptogenic insults induce significant changes in gene expression within a subset of pre-defined GO terms, that is, in groups of functionally linked genes. We also found individual genes for which expression changed across different models of epileptogenesis. Alterations in gene expression appear time-specific and underlie a number of processes that are linked with epileptogenesis, such as cell death and survival, neuronal plasticity, or immune response. Particularly, our analysis highlighted alterations in gene expression in glial cells as well as in genes involved in the immune response, which suggests the importance of gliosis and immune reaction in epileptogenesis.

Animals↗

PubMed2006

Identification of conserved modes of expression profiles during hippocampal development and neuronal differentiation in vitro.

Gene expression profiles can be regarded as sums of simpler modes, analogous to the modes of a vibrating violin string. Decomposition of temporal gene expression profiles into modes by singular value decomposition (SVD) was reported before, but the question as to what degree the SVD modes can be interpreted in terms of biology remains open. We report and compare the results of SVD of published datasets from hippocampal development, neuronal differentiation in vitro, and a control time-series hippocampal dataset. We demonstrate that the first SVD mode reflects the magnitude of expression, interpretable on the Affymetrix platform. In the datasets from gene profiling of hippocampal development and neuronal differentiation, the second mode reflects a monotonous change in expression, either up- or down-regulation, in the time course of experiment. We demonstrate that the top two SVD modes are conserved between datasets and therefore, likely reflect properties of the underlying system (gene expression in hippocampus) rather than of a particular experiment or dataset. Our results also indicate that the magnitude of expression, and the direction of change in expression during hippocampal development, are uncorrelated, suggesting that they are regulated by largely independent mechanisms.

Animals↗

PubMed2004

Comprehensive analysis of the base composition around the transcription start site in Metazoa.

BACKGROUND: The transcription start site of a metazoan gene remains poorly understood, mostly because there is no clear signal present in all genes. Now that several sequenced metazoan genomes have been annotated, we have been able to compare the base composition around the transcription start site for all annotated genes across multiple genomes. RESULTS: The most prominent feature in the base compositions is a significant local variation in G+C content over a large region around the transcription start site. The change is present in all animal phyla but the extent of variation is different between distinct classes of vertebrates, and the shape of the variation is completely different between vertebrates and arthropods. Furthermore, the height of the variation correlates with CpG frequencies in vertebrates but not in invertebrates and it also correlates with gene expression, especially in mammals. We also detect GC and AT skews in all clades (where %G is not equal to %C or %A is not equal to %T respectively) but these occur in a more confined region around the transcription start site and in the coding region. CONCLUSIONS: The dramatic changes in nucleotide composition in humans are a consequence of CpG nucleotide frequencies and of gene expression, the changes in Fugu could point to primordial CpG islands, and the changes in the fly are of a totally different kind and unrelated to dinucleotide frequencies.

AT Rich Sequence↗

PubMed2004

Coordinated and widespread expression of gamma-secretase in vivo: evidence for size and molecular heterogeneity.

Gamma-secretase is a high molecular weight protein complex composed of four subunits, namely, presenilin (PS; 1 or 2), nicastrin, anterior pharynx defective-1 (Aph-1; A or B), and presenilin enhancer-2 (Pen-2), and is responsible for the cleavage of a number of type-1 transmembrane proteins. A fundamental question is whether different gamma-secretase complexes exist in vivo. We demonstrate here by in situ hybridization and by Northern and Western blotting that the gamma-secretase components are widely distributed in all tissues investigated. The expression of the different subunits seems tightly coregulated. However, some variation in the expression of the Aph-1 proteins is observed, Aph-1A being more general and abundantly distributed than Aph-1B. The previously uncharacterized rodent-specific Aph-1C mRNA is highly expressed in the kidney and testis but not in brain or other tissues, indicating some tissue specificity for the Aph-1 component of the gamma-secretase complex. Blue-native electrophoresis revealed size heterogeneity of the mature gamma-secretase complex in various tissues. Using co-immunoprecipitations and blue-native electrophoresis at endogenous protein levels, we find evidence that several independent gamma-secretase complexes can coexist in the same cell type. In conclusion, our results suggest that gamma-secretase is a heterogeneous family of protein complexes widely expressed in the adult organism.

Amino Acid Sequence↗

PubMed2003

Comparison and meta-analysis of microarray data: from the bench to the computer desk.

The upcoming availability of public microarray repositories and of large compendia of gene expression information opens up a new realm of possibilities for microarray data analysis. An essential challenge is the efficient integration of microarray data generated by different research groups on different array platforms. This review focuses on the problems associated with this integration, which are: (1) the efficient access to and exchange of microarray data; (2) the validation and comparison of data from different platforms (cDNA and short and long oligonucleotides); and (3) the integrated statistical analysis of multiple data sets.

Databases, Genetic↗

PubMed2003

Gene profiling of hippocampal neuronal culture.

We performed mRNA expression profiling of mouse primary hippocampal neurones undergoing differentiation in vitro. We show that 2314 genes significantly changed expression during neuronal differentiation. The temporal resolution of our experiment (six time points) permits us to distinguish between gene expression patterns characteristic for the axonal and for the dendritic stages of neurite outgrowth. Cluster analysis reveals that, in the process of in vitro neuronal differentiation, a high level of expression of genes involved in the synthesis of DNA and proteins precedes the up regulation of genes involved in protein transport, energy generation and synaptic functions. We report in detail changes in gene expression for genes involved in the synaptic vesicle cycle. Data for other genes can be accessed at our website. We directly compare expression of 475 genes in the differentiating neurones and the developing mouse hippocampus. We demonstrate that the program of gene expression is accelerated in vitro as compared to the situation in vivo. When this factor is accounted for, the gene expression profiles in vitro and in vivo become very similar (median gene-wise correlation 0.787). Apparently once the cells have taken a neuronal fate, the further program of gene expression is largely independent of histological or anatomical context. Our results also demonstrate that a comparison across the two experimental platforms (cDNA microarrays and oligonucleotide chips) and across different biological paradigms is feasible.

Animals↗