Network-based functional enrichment

<p>Abstract</p> <p>Background</p> <p>Many methods have been developed to infer and reason about molecular interaction networks. These approaches often yield networks with hundreds or thousands of nodes and up to an order of magnitude more edges. It is often desirable to summarize the biological information in such networks. A very common approach is to use gene function enrichment analysis for this task. A major drawback of this method is that it ignores information about the edges in the network being analyzed, i.e., it treats the network simply as a set of genes. In this paper, we introduce a novel method for functional enrichment that explicitly takes network interactions into account.</p> <p>Results</p> <p>Our approach naturally generalizes Fisher’s exact test, a gene set-based technique. Given a function of interest, we compute the subgraph of the network induced by genes annotated to this function. We use the sequence of sizes of the connected components of this sub-network to estimate its connectivity. We estimate the statistical significance of the connectivity empirically by a permutation test. We present three applications of our method: i) determine which functions are enriched in a given network, ii) given a network and an interesting sub-network of genes within that network, determine which functions are enriched in the sub-network, and iii) given two networks, determine the functions for which the connectivity improves when we merge the second network into the first. Through these applications, we show that our approach is a natural alternative to network clustering algorithms.</p> <p>Conclusions</p> <p>We presented a novel approach to functional enrichment that takes into account the pairwise relationships among genes annotated by a particular function. Each of the three applications discovers highly relevant functions. We used our methods to study biological data from three different organisms. Our results demonstrate the wide applicability of our methods. Our algorithms are implemented in C++ and are freely available under the GNU General Public License at our supplementary website. Additionally, all our input data and results are available at <url>http://bioinformatics.cs.vt.edu/~murali/supplements/2011-incob-nbe/</url>.</p

BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway

By diversifying antibody biological effector functions, class switch DNA recombination has a central role in the maturation of the antibody response. Here we show that BCR-signalling synergizes with Toll-like receptor (TLR) signalling to induce class switch DNA recombination. BCR-signalling activates the non-canonical NF-κB pathway and enhances the TLR-dependent canonical NF-κB pathway, thereby inducing activation-induced cytidine deaminase (AID), which is critical for class switch DNA recombination. Escherichia coli lipopolysaccharide (LPS) triggers dual TLR4/BCR-signalling and induces hallmarks of BCR-signalling, including CD79a phosphorylation and Ca2+ mobilization, and activates both the NF-κB pathways to induce AID and class switch DNA recombination in a PI(3)K p85α-dependent fashion. CD40-signalling activates the two NF-κB pathways to induce AID and class switch DNA recombination independent of BCR-signalling. Finally, dual BCR/TLR-engaging NP–lipopolysaccharide effectively elicits class-switched NP-specific IgG3 and IgG2b in mice. Thus, by integrating signals of the non-canonical and canonical NF-κB pathways, BCR and TLRs synergize to induce AID and T-cell-independent class switch DNA recombination

The riddle of the dual expression of IgM and IgD

Signalling through the B cell antigen receptor (BCR) is required for peripheral B lymphocyte maturation, maintenance, activation and silencing. In mature B cells, the antigen receptor normally consists of two isotypes, membrane IgM and IgD (mIgM, mIgD). Although the signals initiated from both isotypes differ in kinetics and intensity, in vivo, the BCR of either isotype seems to be able to compensate for the loss of the other, reflected by the mild phenotypes of mice deficient for mIgM or mIgD. Thus, it is still unclear why mature B cells need expression of mIgD in addition to mIgM. In the current review we suggest that the view that IgD has a simpIy definable function centred around the basic signalling function should be replaced by the assumption that IgD fine tunes humoral responses, modulates B cell selection and homeostasis and thus shapes the B cell repertoire, defining IgD to be a key modulator of the humoral immune response

Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis

The chimeric fusion oncogene early B-cell factor 1-platelet-derived growth factor receptor-β (EBF1-PDGFRB) is a recurrent lesion observed in Philadelphia-like B-acute lymphoblastic leukemia (B-ALL) and is associated with particularly poor prognosis. While it is understood that this fusion activates tyrosine kinase signaling, the mechanisms of transformation and importance of perturbation of EBF1 activity remain unknown. EBF1 is a nuclear transcription factor required for normal B-lineage specification, commitment and development. Conversely, PDGFRB is a receptor tyrosine kinase that is normally repressed in lymphocytes, yet PDGFRB remains a common fusion partner in leukemias. Here, we demonstrate that the EBF1-PDGFRB fusion results in loss of EBF1 function, multimerization and autophosphorylation of the fusion protein, activation of signal transducer and activator of transcription 5 (STAT5) signaling and gain of interleukin-7 (IL-7)-independent cell proliferation. Deregulation and loss of EBF1 function is critically dependent on the nuclear export activity of the transmembrane (TM) domain of PDGFRB. Deletion of the TM domain partially rescues EBF1 function and restores IL-7 dependence, without requiring kinase inhibition. Moreover, we demonstrate that EBF1-PDGFRB synergizes with loss of IKAROS function in a fully penetrant B-ALL in vivo. Thus, we establish that EBF1-PDGFRB is sufficient to drive leukemogenesis through TM-dependent loss of transcription factor function, increased proliferation and synergy with additional genetic insults including loss of IKAROS function.SJ Welsh, ML Churchman, M Togni, CG Mullighan and J Hagma