Ruth Isserlin

University of Toronto | U of T · Department of Cell and Systems Biology

Cell cycle duration changes dramatically during development, starting out fast to generate cells quickly and slowing down over time as the organism matures. The cell cycle can also act as a transcriptional filter to control the expression of long gene transcripts which are partially transcribed in short cycles. Using mathematical simulations of cel...

Androgens are a major driver of prostate cancer (PCa) and continue to be a critical treatment target for advanced disease, which includes castration therapy and antiandrogens. However, resistance to these therapies leading to metastatic castration-resistant prostate cancer (mCRPC), and the emergence of treatment-induced neuroendocrine disease (tNEP...

Patient classification based on clinical and genomic data will further the goal of precision medicine. Interpretability is of particular relevance for models based on genomic data, where sample sizes are relatively small (in the hundreds), increasing overfitting risk netDx is a machine learning method to integrate multi-modal patient data and build...

Patient classification based on clinical and genomic data will further the goal of precision medicine. Interpretability is of particular relevance for models based on genomic data, where sample sizes are relatively small (in the hundreds), increasing overfitting risk netDx is a machine learning method to integrate multi-modal patient data and build...

Aim: We examined methylation changes in cell-free DNA (cfDNA) in metastatic castration-resistant prostate cancer (mCRPC) during treatment. Patients & methods: Genome-wide methylation analysis of sequentially collected cfDNA samples derived from mCRPC patients undergoing androgen-targeting therapy was performed. Results: Alterations in methylation s...

Aim We examined methylation changes in cell-free DNA (cfDNA) in metastatic castration resistant prostate cancer (mCRPC) during treatment. Materials and Methods Genome-wide methylation analysis of sequentially collected cfDNA samples derived from mCRPC patients undergoing androgen-targeting therapy was performed. Results Alterations in methylation...

Cell cycle duration changes dramatically during development, starting out fast to generate cells quickly and slowing down over time as the organism matures. The cell cycle can also act as a transcriptional filter to control the expression of long genes which are partially transcribed in short cycles. Using mathematical simulations of cell prolifera...

RCy3 is an R package in Bioconductor that communicates with Cytoscape via its REST API, providing access to the full feature set of Cytoscape from within the R programming environment. RCy3 has been redesigned to streamline its usage and future development as part of a broader Cytoscape Automation effort. Over 100 new functions have been added, inc...

RCy3 is an R package in Bioconductor that communicates with Cytoscape via its REST API, providing access to the full feature set of Cytoscape from within the R programming environment. RCy3 has been redesigned to streamline its usage and future development as part of a broader Cytoscape Automation effort. Over 100 new functions have been added, inc...

RCy3 is an R package in Bioconductor that communicates with Cytoscape via its REST API, providing access to the full feature set of Cytoscape from within the R programming environment. RCy3 has been redesigned to streamline its usage and future development as part of a broader Cytoscape Automation effort. Over 100 new functions have been added, inc...

RCy3 is an R package in Bioconductor that communicates with Cytoscape via its REST API, providing access to the full feature set of Cytoscape from within the R programming environment. RCy3 has been redesigned to streamline its usage and future development as part of a broader Cytoscape Automation effort. Over 100 new functions have been added, inc...

The mammalian brain is complex, with multiple cell types performing a variety of diverse functions, but exactly how each cell type is affected in aging remains largely unknown. Here we performed a single-cell transcriptomic analysis of young and old mouse brains. We provide comprehensive datasets of aging-related genes, pathways and ligand–receptor...

Purpose Glioblastoma (GBM) is the most aggressive adult brain cancer, with a 15 month median survivorship attributed to the existence of treatment-refractory brain tumor initiating cells (BTICs). In order to better understand the mechanisms regulating the tumorigenic properties of this population, we studied the role of the polycomb group member BM...

Background Global DNA methylation alterations are hallmarks of cancer. The tumor-suppressive TET enzymes, which are involved in DNA demethylation, are decreased in prostate cancer (PCa); in particular, TET2 is specifically targeted by androgen-dependent mechanisms of repression in PCa and may play a central role in carcinogenesis. Thus, the identif...

Patient classification has widespread biomedical and clinical applications, including diagnosis, prognosis, and treatment response prediction. A clinically useful prediction algorithm should be accurate, generalizable, be able to integrate diverse data types, and handle sparse data. A clinical predictor based on genomic data needs to be interpretab...

Pathway enrichment analysis helps researchers gain mechanistic insight into gene lists generated from genome-scale (omics) experiments. This method identifies biological pathways that are enriched in a gene list more than would be expected by chance. We explain the procedures of pathway enrichment analysis and present a practical step-by-step guide...

The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult...

Patient classification has widespread biomedical and clinical applications, including diagnosis, prognosis and treatment response prediction. A clinically useful prediction algorithm should be accurate, generalizable, be able to integrate diverse data types, and handle sparse data. A clinical predictor based on genomic data needs to be easily inter...

Pathway enrichment analysis helps gain mechanistic insight into large gene lists typically resulting from genome scale (– omics ) experiments. It identifies biological pathways that are enriched in the gene list more than expected by chance. We explain pathway enrichment analysis and present a practical step-by-step guide to help interpret gene lis...

Endurance exercise improves cardiac performance and affords protection against cardiovascular diseases but the signalling events that mediate these benefits are largely unexplored. Phosphorylation is an widely studied post-translational modification involved in intracellular signalling, and to discover novel phosphorylation events associated with e...

Identification of drug targets and mechanism of action (MoA) for new and uncharacterized anticancer drugs is important for optimization of treatment efficacy. Current MoA prediction largely relies on prior information including side effects, therapeutic indication, and chemo-informatics. Such information is not transferable or applicable for newly...

Identification of drug targets and mechanism of action (MoA) for new and uncharacterlzed drugs is important for optimization of drug efficacy. Current MoA prediction approaches largely rely on prior information including side effects, therapeutic indication and/or chemo-informatics. Such information is not transferable or applicable for newly ident...

Significance The present study demonstrates the utility of global phosphoproteomic profiling of diseased cardiac tissue to identify signaling pathways and other biological processes disrupted in cardiomyopathy. Perturbed Notch-1 signaling was identified by bioinformatics analyses of phosphoprotein patterns present in affected cardiac tissue in a tr...

This case study of the impact of publications in the area of Neurosciences and Mental Health was completed as part of an institutional analysis of health research activity at the University of Toronto. Our data show that selecting top researchers by total publication output favoured clinical research over all other research disciplines active in th...

Networks often contain regions of tightly connected nodes, or clusters, that highlight their shared relationships. An effective way to create a visual summary of a network is to identify clusters and annotate them with an enclosing shape and a summarizing label. Cytoscape provides the ability to annotate a network with shapes and labels, however th...

Umbilical cord blood (CB) is a convenient and broadly used source of hematopoietic stem cells (HSCs) for allogeneic stem cell transplantation. However, limiting numbers of HSCs remain a major constraint for its clinical application. Although one feasible option would be to expand HSCs to improve therapeutic outcome, available protocols and the mole...

Background: Despite the significant global loss of DNA hydroxymethylation marks in prostate cancer tissues, the locus-specific role of hydroxymethylation in prostate tumorigenesis is unknown. We characterized hydroxymethylation and methylation marks by performing whole-genome next-generation sequencing in representative normal and prostate cancer-...

To investigate miRNA function in human acute myeloid leukemia (AML) stem cells (LSC), we generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of AML samples. For one signature miRNA, miR-126, high bioactivity aggregated all in vivo patient sample LSC activity into a single sorted population, tight...

Aberrant epigenetic modification in the form of regional hypermethylation and global hypomethylation has been implicated in the dysregulation of gene expression in various cancers, including prostate cancer (PCa). Recently discovered 5-hydroxymethylated marks (5hmC), considered to be key intermediates in the process of DNA demethylation, have also...

Networks that represent connections between individuals can be valuable analytic tools. The Social Network Cytoscape app is capable of creating a visual summary of connected individuals automatically. It does this by representing relationships as networks where each node denotes an individual and an edge linking two individuals represents a connect...

Significance Cells interact with materials, such as those used in implants, through an adsorbed protein layer that causes changes in cell behavior and gene expression. We have identified the activation of signaling pathways in the cell by a material by unbiased screening of changes in phosphorylation patterns in the cell after material exposure to...

Networks that represent connections between individuals can be valuable analytic tools. The Social Network Cytoscape app is capable of creating a visual summary of connected individuals automatically. It does this by representing relationships as networks where each node denotes an individual and an edge linking two individuals represents a connect...

Solute carrier (SLC) membrane transport proteins control essential physiological functions, including nutrient uptake, ion transport, and waste removal. SLCs interact with several important drugs, and a quarter of the more than 400 SLC genes are associated with human diseases. Yet, compared to other gene families of similar stature, SLCs are relati...

Fertilization triggers a dynamic symphony of molecular transformations induced by a rapid rise in intracellular calcium. Most prominent are surface alterations, metabolic activation, cytoskeletal reorganization, and cell-cycle reentry. While the activation process appears to be broadly evolutionarily conserved, and protein phosphorylation is known...

To discover signalling events associated with acute exercise we investigated the cardiac phosphoproteome response to a standardised exercise test. Male Wistar rats (346 ± 18 g, n = 6 per group) performed a treadmill test to measure their VO2peak and were killed either immediately after or 3 h after cessation of the exercise; control rats did not pe...

To understand the molecular pathways underlying the cardiac preconditioning effect of short-term caloric restriction (CR). Lifelong CR has been suggested to reduce the incidence of cardiovascular disease through a variety of mechanisms. However, prolonged adherence to a CR life-style is difficult. Here we reveal the pathways that are modulated by s...

Adiponectin mediates antidiabetic effects via increasing hepatic insulin sensitivity and direct metabolic effects. In this study we conducted a comprehensive and unbiased metabolomic profiling of liver tissue from adiponectin knockout (AdKO) mice, with and without adiponectin supplementation, fed high fat diet (HFD) to derive insight into the mecha...

Networks that represent connections between individuals can be valuable analytic tools. The Social Network Cytoscape app is capable of creating a visual summary of connected individuals automatically. It does this by representing relationships as networks where each node denotes an individual and an edge linking two individuals represents a connect...

Apoptosis is a hallmark of multiple etiologies of heart failure, including dilated cardiomyopathy. Since microRNAs are master regulators of cardiac development and key effectors of intracellular signaling, they represent novel candidates for understanding the mechanisms driving the increased dysfunction and loss of cardiomyocytes during cardiovascu...

Protein phosphorylation plays a central role in the dynamic intracellular signaling and the control of biochemical pathways in all living cells. Recent advances in high-performance MS/MS-based technology make the large-scale identification and quantification of phosphorylation sites possible. Here, we review the full data generation pipeline, start...

High-throughput OMICs experiments generate signals for millions of entities (i.e. genes, proteins, metabolites or any measurable biological entity) in the cell. In an effort to summarize and explore these signals, expression results are examined in the context of known pathways and processes, through enrichment analysis to generate a set of pathway...

The availability of human genome sequence has transformed biomedical research over the past decade. However, an equivalent map for the human proteome with direct measurements of proteins and peptides does not exist yet. Here we present a draft map of the human proteome using high-resolution Fourier-transform mass spectrometry. In-depth proteomic pr...

Multiple sclerosis is a chronic demyelinating disorder characterised by the infiltration of auto-reactive immune cells from the periphery into the central nervous system resulting in axonal injury and neuronal cell death. Experimental autoimmune encephalomyelitis represents the best characterised animal model as common clinical, histological and im...

Global expression profiling is a promising technique to help uncover perturbations associated with heart disease. With the large amount of expression data generated, we demonstrate how a list of differentially expressed proteins or genes can be translated into a list of perturbed pathways and functions using conventional overrepresentation analysis...

Protein kinase signaling regulates human hematopoietic stem/progenitor cell (HSPC) fate, yet little is known about critical pathway substrates. To address this, we have developed and applied a large-scale, empirically optimized phosphopeptide affinity enrichment strategy with high-throughput 2D LC-MS/MS screening to evaluate the phosphoproteome of...

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Brain tumors are the most common cause of cancer-related death in childhood. Ependymomas, are the third most common pediatric brain tumor. The disease remains incurable for about 45% of patients even after gross total resection and radiotherapy. Despite showing a very ho...

Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinical...

Gene-set enrichment analysis finds functionally coherent gene-sets, such as pathways, that are statistically overrepresented in a given gene list. Ideally, the number of resulting sets is smaller than the number of genes in the list, thus simplifying interpretation. However, the increasing number and redundancy of -gene-sets used by many current en...

To study proteins in the context of a cellular system, it is essential that the molecules with which a protein interacts are identified and the functional consequence of each interaction is understood. A plethora of resources now exist to capture molecular interaction data from the many laboratories generating…

When biological networks are studied, it is common to look for clusters, i.e. sets of nodes that are highly inter-connected. To understand the biological meaning of a cluster, the user usually has to sift through many textual annotations that are associated with biological entities. The WordCloud Cytoscape plugin generates a visual summary of these...

The draft sequence of the human genome became available almost a decade ago but the encoded proteome is not being explored to its fullest. Our bibliometric analysis of several large protein families, including those known to be "druggable", reveals that, even today, most papers focus on proteins that were known prior to 2000. It is evident that one...

Most protein research focuses on those known before the human genome was mapped. Work on the slew discovered since, urge Aled M. Edwards and his colleagues.

The Biomolecular Interaction Network Database (BIND) is a major source of curated biomolecular interactions, which has been unmaintained for the last few years, a trend which will eventually result in the loss of a significant amount of unique biomolecular interaction information, mostly as database identifiers become out of date. To help reverse t...

Enrichment Map analysis using additional gene-set sources. (4.75 MB DOC)

GSEA enrichment results for estrogen treatment of breast cancer cells; gene-sets relating to the microtubule cytoskeleton are highlighted. (0.68 MB XLS)

Gene expression and annotation tables for genes analyzed in Use case 3 (post-analysis); genes discussed in the main text are highlighted. (0.11 MB XLS)

Enrichment Map for Alzheimer disease genes using Fisher's Exact Test and comparison to MCM. (1.98 MB DOC)

Enrichment Maps for estrogen treatment using different statistics for differential expression; ratio-of-class-means generates noisier results than the t-test. (1.72 MB DOC)

Gene-set enrichment analysis is a useful technique to help functionally characterize large gene lists, such as the results of gene expression experiments. This technique finds functionally coherent gene-sets, such as pathways, that are statistically over-represented in a given gene list. Ideally, the number of resulting sets is smaller than the num...

Cardiac-specific overexpression of a constitutively active form of calcineurin A (CNA) leads directly to cardiac hypertrophy in the CNA mouse model. Because cardiac hypertrophy is a prominent characteristic of many cardiomyopathies, we deduced that delineating the proteomic profile of ventricular tissue from this model might identify novel, widely...

Global protein expression profiling can potentially uncover perturbations associated with common forms of heart disease. We have used shotgun MS/MS to monitor the state of biological systems in cardiac tissue correlating with disease onset, cardiac insufficiency and progression to heart failure in a time-course mouse model of dilated cardiomyopathy...

Protein complexes and protein-protein interactions are essential for almost all cellular processes. Here, we establish a mammalian affinity purification and lentiviral expression (MAPLE) system for characterizing the subunit compositions of protein complexes. The system is flexible (i.e. multiple N- and C-terminal tags and multiple promoters), is c...

Recent advances in mass spectrometry and bioinformatics have provided the means to characterize complex protein landscapes from a wide variety of organisms and cell types. Development of standard proteomes exhibiting all of the proteins involved in normal physiology will facilitate the delineation of disease mechanisms. Here, we examine the wild-ty...

Large-scale quantitative shotgun tandem mass spectrometry serves as a flexible proteomic platform for the systematic investigation of molecular processes perturbed by disease and the potential discovery of clinically relevant protein biomarkers associated with a particular pathology. Multiple innovative profiling techniques have been introduced wit...

Defective mobilization of Ca2+ by cardiomyocytes can lead to cardiac insufficiency, but the causative mechanisms leading to congestive heart failure (HF) remain unclear. In the present study we performed exhaustive global proteomics surveys of cardiac ventricle isolated from a mouse model of cardiomyopathy overexpressing a phospholamban mutant, R9C...

Author Summary Many functions performed within a living cell are mediated by specific interactions between proteins. Precise geometric and chemical matches between segments of the protein structures facilitate those interactions. Such binding surfaces are often evolutionarily conserved elements of protein structures known as conserved domains that...

Cytoscape is a free software package for visualizing, modeling and analyzing molecular and genetic interaction networks. This protocol explains how to use Cytoscape to analyze the results of mRNA expression profiling, and other functional genomics and proteomics experiments, in the context of an interaction network obtained for genes of interest. F...

Cytoscape Session File Containing the Validated and Predicted Protein Interactions A Cytoscape session file containing the complete set of predicted interactions as well as the networks in Figures 2, 3, S1, and S2. The networks can be viewed using the Cytoscape network visualization tool freely available at http://www.cytoscape.org. (2.0 MB ZIP)

The Overlap between the Predicted Interaction Network and a Comprehensive Set of Literature-Curated Interactions [33] The predicted interactions were compared to a new and exhaustive set of curated interactions extracted from the literature that includes physical interactions from both high-throughput and directed studies as well as genetic interac...

IP-Western Results for the Novel Interactions Predicted by D-MIST Bait proteins were purified using FLAG antibodies, and their interacting proteins were detected by antibodies specific to C-terminal HA or Myc3 epitopes. (325 KB PDF)

The Domain-Binding Profiles Derived by D-MIST Each domain-binding profile is specified as a list of sequence motifs. The sequence motifs are used as input to a PSSM search program [56]. Source code available at http://www.people.fas.harvard.edu/~junliu/index1.html#Computational_Biology. (2.7 MB TXT)

A major aim of proteomic profiling of disease is to uncover the mechanistic basis of a given pathology. High-throughput experimental techniques continue to advance rapidly, but are still plagued by high rates of false negatives, false positives, and other spurious findings. By reducing a disease profile to a subset of differentially expressed prote...

The Biomolecular Interaction Network Database (BIND) (http://bind.ca) archives biomolecular interaction, reaction, complex and pathway information. Our aim is to curate the details about molecular interactions that arise from published experimental research and to provide this information, as well as tools to enable data analysis, freely to researc...