Systematic Evaluation of Molecular Networks for Discovery of Disease Genes

Huang, Justin K.; Carlin, Daniel E.; Yu, Michael; Zhang, Wei; Kreisberg, Jason F.; Tamayo, Pablo; Ideker, Trey

doi:10.1016/j.cels.2018.03.001

Cited by 231 publications

(267 citation statements)

References 91 publications

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“…Together the two approaches helped overcome their respective inherent limitations: gaps in identification because of the stochastic nature of LFQ, and compression of the magnitude change in TMT due to overlapping contaminants and MS/MS reporter signals . Interpretation of the changes to the proteome were greatly assisted with pathway analysis tools like IPA, REACTOME, and STRING, but even after discovering a functionally connected network with these tools, its size and statistical significance were enhanced with a substantial effort in manual curation, a strategy that has been emphasized by others …”

Section: Resultsmentioning

confidence: 99%

Plasma Proteome Signature of Sepsis: a Functionally Connected Protein Network

et al. 2019

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Sepsis is an extreme host response to infection that leads to loss of organ function and cardiovascular integrity. Mortality from sepsis is on the rise. Despite more than three decades of research and clinical trials, specific diagnostic and therapeutic strategies for sepsis are still absent. The use of LFQ‐ and TMT‐based quantitative proteomics is reported here to study the plasma proteome in five mouse models of sepsis. A knowledge‐based interpretation of the data reveals a protein network with extensive connectivity through documented functional or physical interactions. The individual proteins in the network all have a documented role in sepsis and are known to be extracellular. The changes in protein abundance observed in the mouse models of sepsis have for the most part the same directionality (increased or decreased abundance) as reported in the literature for human sepsis. This network has been named the Plasma Proteome Signature of Sepsis (PPSS). The PPSS is a quantifiable molecular readout that can supplant the current symptom‐based approach used to diagnose sepsis. This type of molecular interpretation of sepsis, its progression, and its response to therapeutic intervention are an important step in advancing our understanding of sepsis, and for discovering and evaluating new therapeutic strategies.

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Section: Resultsmentioning

confidence: 99%

Plasma Proteome Signature of Sepsis: a Functionally Connected Protein Network

et al. 2019

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“…This analysis identified 394 genes for which methylation values showed conserved time-dependent behavior across species (empirical p < 0.05, Figure S3, Table S2 ). To understand the underlying gene functions we mapped them onto the Parsimonious Composite Network (PCNet), a database of approximately 2⨉10 6 molecular interactions capturing physical and functional relationships among genes and gene products, in which each interaction has support from multiple sources (Huang et al 2018) . The genes clustered into five highly interconnected network modules ( Figure 3 ), nearly all of which were enriched for developmental functions.…”

Section: Resultsmentioning

confidence: 99%

Quantitative translation of dog-to-human aging by conserved remodeling of epigenetic networks

Wang

Hogan

et al. 2019

Preprint

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Mammals progress through similar physiological stages during life, from early development to puberty, aging, and death. Yet, the extent to which this conserved physiology reflects conserved molecular events is unclear. Here, we map common epigenetic changes experienced by mammalian genomes as they age, focusing on evolutionary comparisons of humans to dogs, an emerging model of aging. Using targeted sequencing, we characterize the methylomes of 104Labrador retrievers spanning a 16 year age range, achieving >150X coverage within mammalian syntenic blocks. Comparison with human methylomes reveals a nonlinear relationship which translates dog to human years, aligns the timing of major physiological milestones between the two species, and extends to mice. Conserved changes center on specific developmental gene networks which are sufficient to capture the effects of anti-aging interventions in multiple mammals. These results establish methylation not only as a diagnostic age readout but as a cross-species translator of physiological aging milestones.

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“…Collecting all connections together generated regulatory networks for the Paneth cell enriched enteroid (PCeE) and goblet cell enriched enteroid (GCeE) datasets. This approach to collating networks (regulatory or otherwise) has been used for a wide variety of research aims, such as the identification of genes functioning in a variety of diseases (75,76), the prioritisation of therapeutic targets (77) and for a more general understanding of gene regulation in biological systems (78,79). The application of prior knowledge avoids the need for reverse engineering / inference of regulatory network connections, which is time consuming, computationally expensive and requires large quantities of high quality data (80).…”

Section: Discussionmentioning

confidence: 99%

Regulatory network analysis of Paneth cell and goblet cell enriched gut organoids using transcriptomics approaches

Treveil

Sudhakar

Matthews

et al. 2019

Preprint

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The epithelial lining of the small intestine consists of multiple cell types, including Paneth cells and goblet cells, that work in cohort to maintain gut health. 3D in vitro cultures of human primary epithelial cells, called organoids, have become a key model to study the functions of Paneth cells and goblet cells in normal and diseased conditions. Advances in these models include the ability to skew differentiation to particular lineages, providing a useful tool to study cell type specific function/dysfunction in the context of the epithelium. Here, we use comprehensive profiling of mRNA, microRNA and long noncoding RNA expression to confirm that Paneth cell and goblet cell enrichment of murine small intestinal organoids (enteroids) establishes a physiologically accurate model. We employ network analysis to infer the regulatory landscape altered by skewing differentiation, and using knowledge of cell type specific markers, we predict key regulators of cell type specific functions: Cebpa, Jun, Nr1d1 and Rxra specific to Paneth cells, Gfi1b and Myc specific for goblet cells and Ets1, Nr3c1 and Vdr shared between them. Links identified between these regulators and cellular phenotypes of inflammatory bowel disease (IBD) suggest that global regulatory rewiring during or after differentiation of Paneth cells and goblet cells could contribute to IBD aetiology. Future application of cell type enriched enteroids combined with the presented computational workflow can be used to disentangle multifactorial mechanisms of these cell types and propose regulators whose pharmacological targeting could be advantageous in treating IBD patients with Crohn's disease or ulcerative colitis.

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Systematic Evaluation of Molecular Networks for Discovery of Disease Genes

Cited by 231 publications

References 91 publications

Plasma Proteome Signature of Sepsis: a Functionally Connected Protein Network

Plasma Proteome Signature of Sepsis: a Functionally Connected Protein Network

Quantitative translation of dog-to-human aging by conserved remodeling of epigenetic networks

Regulatory network analysis of Paneth cell and goblet cell enriched gut organoids using transcriptomics approaches

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