Project description:The aim of the present study identify putative macromolecular interactions in human peripheral blood based on significant correlations at the transcriptional level. We found that significant transcript correlations within the giant matrix reflect experimentally documented interactions involving select ubiquitous blood relevant transcription factors (CREB1, GATA1, and the glucocorticoid receptor (GR, NR3C1)).
Project description:The aim of the present study identify putative macromolecular interactions in human peripheral blood based on significant correlations at the transcriptional level. We found that significant transcript correlations within a giant matrix including also mRNAs from the same project reflect experimentally documented interactions
Project description:BackgroundPhysical molecular interactions are the basis of intracellular signalling and gene regulatory networks, and comprehensive, accessible databases are needed for their discovery. Highly correlated transcripts may reflect important functional associations, but identification of such associations from primary data are cumbersome. We have constructed and adapted a user-friendly web application to discover and identify putative macromolecular associations in human peripheral blood based on significant correlations at the transcriptional level.MethodsThe blood transcriptome was characterized by quantification of 17,328 RNA species, including 341 mature microRNAs in 105 clinically well-characterized postmenopausal women. Intercorrelation of detected transcripts signal levels generated a matrix with > 150 million correlations recognizing the human blood RNA interactome. The correlations with calculated adjusted p-values were made easily accessible by a novel web application.ResultsWe found that significant transcript correlations within the giant matrix reflect experimentally documented interactions involving select ubiquitous blood relevant transcription factors (CREB1, GATA1, and the glucocorticoid receptor (GR, NR3C1)). Their responsive genes recapitulated up to 91% of these as significant correlations, and were replicated in an independent cohort of 1204 individual blood samples from the Framingham Heart Study. Furthermore, experimentally documented mRNAs/miRNA associations were also reproduced in the matrix, and their predicted functional co-expression described. The blood transcript web application is available at http://app.uio.no/med/klinmed/correlation-browser/blood/index.php and works on all commonly used internet browsers.ConclusionsUsing in silico analyses and a novel web application, we found that correlated blood transcripts across 105 postmenopausal women reflected experimentally proven molecular associations. Furthermore, the associations were reproduced in a much larger and more heterogeneous cohort and should therefore be generally representative. The web application lends itself to be a useful hypothesis generating tool for identification of regulatory mechanisms in complex biological data sets.
Project description:Neuronal migration constitutes an important step in corticogenesis; dysregulation of the molecular mechanisms mediating this crucial step in neurodevelopment may result in various neuropsychiatric disorders. By curating experimental data from published literature, we identified eight functional modules involving Disrupted-in-schizophrenia 1 (DISC1) and its interacting proteins that regulate neuronal migration. We then identified miRNAs and transcription factors (TFs) that form functional feedback loops and regulate gene expression of the DISC1 interactome. Using this curated data, we conducted in-silico modeling of the DISC1 interactome involved in neuronal migration and identified the proteins that either facilitate or inhibit neuronal migrational processes. We also studied the effect of perturbation of miRNAs and TFs in feedback loops on the DISC1 interactome. From these analyses, we discovered that STAT3, TCF3, and TAL1 (through feedback loop with miRNAs) play a critical role in the transcriptional control of DISC1 interactome thereby regulating neuronal migration. To the best of our knowledge, regulation of the DISC1 interactome mediating neuronal migration by these TFs has not been previously reported. These potentially important TFs can serve as targets for undertaking validation studies, which in turn can reveal the molecular processes that cause neuronal migration defects underlying neurodevelopmental disorders. This underscores the importance of the use of in-silico techniques in aiding the discovery of mechanistic evidence governing important molecular and cellular processes. The present work is one such step towards the discovery of regulatory factors of the DISC1 interactome that mediates neuronal migration.