Mapping genetic interactions in cancer: a road to rational combination therapies.

The discovery of synthetic lethal interactions between poly (ADP-ribose) polymerase (PARP) inhibitors and BRCA genes, which are involved in homologous recombination, led to the approval of PARP inhibition as a monotherapy for patients with BRCA1/2-mutated breast or ovarian cancer. Studies following the initial observation of synthetic lethality demonstrated that the reach of PARP inhibitors is well beyond just BRCA1/2 mutants. Insights into the mechanisms of action of anticancer drugs are fundamental for the development of targeted monotherapies or rational combination treatments that will synergize to promote cancer cell death and overcome mechanisms of resistance. The development of targeted therapeutic agents is premised on mapping the physical and functional dependencies of mutated genes in cancer. An important part of this effort is the systematic screening of genetic interactions in a variety of cancer types. Until recently, genetic-interaction screens have relied either on the pairwise perturbations of two genes or on the perturbation of genes of interest combined with inhibition by commonly used anticancer drugs. Here, we summarize recent advances in mapping genetic interactions using targeted, genome-wide, and high-throughput genetic screens, and we discuss the therapeutic insights obtained through such screens. We further focus on factors that should be considered in order to develop a robust analysis pipeline. Finally, we discuss the integration of functional interaction data with orthogonal methods and suggest that such approaches will increase the reach of genetic-interaction screens for the development of rational combination therapies

The road ahead in genetics and genomics

In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field of genetics and genomics. Keeping their particular research area in mind, they take stock of the current state of play and emphasize the work that remains to be done over the next few years so that, ultimately, the benefits of genetic and genomic research can be felt by everyone

System level dynamics of post-translational modifications

Attempts to characterize cellular behaviors with static, univariate measurements cannot fully capture biological complexity and lead to an inadequate interpretation of cellular processes. Significant biological insight can be gleaned by considering the contribution of dynamic protein post-translational modifications (PTMs) utilizing systems-level quantitative analysis. High-resolution mass spectrometry coupled with computational modeling of dynamic signal–response relationships is a powerful tool to reveal PTM-mediated regulatory networks. Recent advances using this approach have defined network kinetics of growth factor signaling pathways, identified systems level responses to cytotoxic perturbations, elucidated kinase–substrate relationships, and unraveled the dynamics of PTM cross-talk. Innovations in multiplex measurement capacity, PTM annotation accuracy, and computational integration of datasets promise enhanced resolution of dynamic PTM networks and further insight into biological intricacies

In Silico Approaches and the Role of Ontologies in Aging Research

The 2013 Rostock Symposium on Systems Biology and Bioinformatics in Aging Research was again dedicated to dissecting the aging process using in silico means. A particular focus was on ontologies, as these are a key technology to systematically integrate heterogeneous information about the aging process. Related topics were databases and data integration. Other talks tackled modeling issues and applications, the latter including talks focussed on marker development and cellular stress as well as on diseases, in particular on diseases of kidney and skin

MicroRNAs in the stressed heart: Sorting the signal from the noise

The short noncoding RNAs, known as microRNAs, are of undisputed importance in cellular signaling during differentiation and development, and during adaptive and maladaptive responses of adult tissues, including those that comprise the heart. Cardiac microRNAs are regulated by hemodynamic overload resulting from exercise or hypertension, in the response of surviving myocardium to myocardial infarction, and in response to environmental or systemic disruptions to homeostasis, such as those arising from diabetes. A large body of work has explored microRNA responses in both physiological and pathological contexts but there is still much to learn about their integrated actions on individual mRNAs and signaling pathways. This review will highlight key studies of microRNA regulation in cardiac stress and suggest possible approaches for more precise identification of microRNA targets, with a view to exploiting the resulting data for therapeutic purposes

High resolution mapping of Twist to DNA in Drosophila embryos: Efficient functional analysis and evolutionary conservation

Cis-regulatory modules (CRMs) function by binding sequence specific transcription factors, but the relationship between in vivo physical binding and the regulatory capacity of factor-bound DNA elements remains uncertain. We investigate this relationship for the well-studied Twist factor in Drosophila melanogaster embryos by analyzing genome-wide factor occupancy and testing the functional significance of Twist occupied regions and motifs within regions. Twist ChIP-seq data efficiently identified previously studied Twist-dependent CRMs and robustly predicted new CRM activity in transgenesis, with newly identified Twist-occupied regions supporting diverse spatiotemporal patterns (>74% positive, n = 31). Some, but not all, candidate CRMs require Twist for proper expression in the embryo. The Twist motifs most favored in genome ChIP data (in vivo) differed from those most favored by Systematic Evolution of Ligands by EXponential enrichment (SELEX) (in vitro). Furthermore, the majority of ChIP-seq signals could be parsimoniously explained by a CABVTG motif located within 50 bp of the ChIP summit and, of these, CACATG was most prevalent. Mutagenesis experiments demonstrated that different Twist E-box motif types are not fully interchangeable, suggesting that the ChIP-derived consensus (CABVTG) includes sites having distinct regulatory outputs. Further analysis of position, frequency of occurrence, and sequence conservation revealed significant enrichment and conservation of CABVTG E-box motifs near Twist ChIP-seq signal summits, preferential conservation of ±150 bp surrounding Twist occupied summits, and enrichment of GA- and CA-repeat sequences near Twist occupied summits. Our results show that high resolution in vivo occupancy data can be used to drive efficient discovery and dissection of global and local cis-regulatory logic

Assessing the functional structure of genomic data

Motivation: The availability of genome-scale data has enabled an abundance of novel analysis techniques for investigating a variety of systems-level biological relationships. As thousands of such datasets become available, they provide an opportunity to study high-level associations between cellular pathways and processes. This also allows the exploration of shared functional enrichments between diverse biological datasets, and it serves to direct experimenters to areas of low data coverage or with high probability of new discoveries