Identification of critical paralog groups with indispensable roles in the regulation of signaling flow

Extensive cross-talk between signaling pathways is required to integrate the myriad of extracellular signal combinations at the cellular level. Gene duplication events may lead to the emergence of novel functions, leaving groups of similar genes - termed paralogs - in the genome. To distinguish critical paralog groups (CPGs) from other paralogs in human signaling networks, we developed a signaling network-based method using cross-talk annotation and tissue-specific signaling flow analysis. 75 CPGs were found with higher degree, betweenness centrality, closeness, and ‘bowtieness’ when compared to other paralogs or other proteins in the signaling network. CPGs had higher diversity in all these measures, with more varied biological functions and more specific post-transcriptional regulation than non-critical paralog groups (non-CPG). Using TGF-beta, Notch and MAPK pathways as examples, SMAD2/3, NOTCH1/2/3 and MEK3/6-p38 CPGs were found to regulate the signaling flow of their respective pathways. Additionally, CPGs showed a higher mutation rate in both inherited diseases and cancer, and were enriched in drug targets. In conclusion, the results revealed two distinct types of paralog groups in the signaling network: CPGs and non-CPGs. Thus highlighting the importance of CPGs as compared to non-CPGs in drug discovery and disease pathogenesis

Amelioration of prenatal alcohol effects by environmental enrichment in a mouse model of FASD

Maternal alcohol consumption during pregnancy results in a spectrum of behavioural and cognitive deficits collectively known as Fetal Alcohol Spectrum Disorders (FASD). Currently, little is know about if and how the external environment may modulate these deficits. I have used C57BL/6 mice to study this interaction between prenatal alcohol exposure and the postnatal environment. Alcohol exposure during synaptogenesis produces high levels of anxiety-like traits and decreased memory performance. Alcohol-exposed mice (and matched unexposed controls) were put in \u27environmentally-enriched\u27 conditions of voluntary exercise, physical activities and cognitive stimulation to ascertain the effects of a positive postnatal environment. The results show that environmental enrichment ameliorates anxiety-like behaviour and memory deficits of alcohol-exposed mice. However this recovery is incomplete, indicative of the long-lasting, potentially permanent damage of prenatal alcohol exposure on the developing brain. In follow-up studies, I have uncovered gene expression changes in the hippocampus that are associated with behavioural and cognitive amelioration. To accomplish this, I have used mouse hippocampal RNA for microarray and RNA-Seq. My results have identified several key genes and molecular pathways that are associated with synaptic and structural plasticity, neurogenesis, long-term potentiation and angiogenesis. The behavioural and molecular results of this project represent a novel finding in the field of FASD research. The genes and pathways uncovered provide a possible explanation to understand FASD. They are also potential targets when formulating behavioural and pharmacological rehabilitative therapies

Essentiality and centrality in protein interaction networks revisited

BACKGROUND: Minimum dominating sets (MDSet) of protein interaction networks allow the control of underlying protein interaction networks through their topological placement. While essential proteins are enriched in MDSets, we hypothesize that the statistical properties of biological functions of essential genes are enhanced when we focus on essential MDSet proteins (e-MDSet). RESULTS: Here, we determined minimum dominating sets of proteins (MDSet) in interaction networks of E. coli, S. cerevisiae and H. sapiens, defined as subsets of proteins whereby each remaining protein can be reached by a single interaction. We compared several topological and functional parameters of essential, MDSet, and essential MDSet (e-MDSet) proteins. In particular, we observed that their topological placement allowed e-MDSet proteins to provide a positive correlation between degree and lethality, connect more protein complexes, and have a stronger impact on network resilience than essential proteins alone. In comparison to essential proteins we further found that interactions between e-MDSet proteins appeared more frequently within complexes, while interactions of e-MDSet proteins between complexes were depleted. Finally, these e-MDSet proteins classified into functional groupings that play a central role in survival and adaptability. CONCLUSIONS: The determination of e-MDSet of an organism highlights a set of proteins that enhances the enrichment signals of biological functions of essential proteins. As a consequence, we surmise that e-MDSets may provide a new method of evaluating the core proteins of an organism

Λειτουργική ανάλυση του γονιδίου FRA10AC1 του ανθρώπου στο πλαίσιο του δικτύου πρωτεϊνικών αλληλεπιδράσεων του σωματίου συναρμογής

Σημείωση: διατίθεται συμπληρωματικό υλικό σε ξεχωριστό αρχείο