Biomedical subjects

Carl Troein

Publications and source records attributed to Carl Troein.

8 recordsLinked to original sources

PubMed2006

Transcriptional dynamics of the embryonic stem cell switch.

Recent ChIP experiments of human and mouse embryonic stem cells have elucidated the architecture of the transcriptional regulatory circuitry responsible for cell determination, which involves the transcription factors OCT4, SOX2, and NANOG. In addition to regulating each other through feedback loops, these genes also regulate downstream target genes involved in the maintenance and differentiation of embryonic stem cells. A search for the OCT4-SOX2-NANOG network motif in other species reveals that it is unique to mammals. With a kinetic modeling approach, we ascribe function to the observed OCT4-SOX2-NANOG network by making plausible assumptions about the interactions between the transcription factors at the gene promoter binding sites and RNA polymerase (RNAP), at each of the three genes as well as at the target genes. We identify a bistable switch in the network, which arises due to several positive feedback loops, and is switched on/off by input environmental signals. The switch stabilizes the expression levels of the three genes, and through their regulatory roles on the downstream target genes, leads to a binary decision: when OCT4, SOX2, and NANOG are expressed and the switch is on, the self-renewal genes are on and the differentiation genes are off. The opposite holds when the switch is off. The model is extremely robust to parameter changes. In addition to providing a self-consistent picture of the transcriptional circuit, the model generates several predictions. Increasing the binding strength of NANOG to OCT4 and SOX2, or increasing its basal transcriptional rate, leads to an irreversible bistable switch: the switch remains on even when the activating signal is removed. Hence, the stem cell can be manipulated to be self-renewing without the requirement of input signals. We also suggest tests that could discriminate between a variety of feedforward regulation architectures of the target genes by OCT4, SOX2, and NANOG.

Animals↗

PubMed2006

An introduction to BioArray Software Environment.

BioArray Software Environment (BASE) is a web-based software package for storing, searching, and analyzing locally generated microarray data and information surrounding microarray production. The workflow begins in sample management and, optionally, microtiter plate tracking and ends in visualization and analysis of entire experiments. The relative ease with which new analysis plug-ins can be added has given rise to a plethora of third-party tools, and the licensing terms (GNU GPL) encourage local modifications of the software. This introduction to BASE describes the basics of working with the software, both in general and in more detail for the various parts. It also provides some hints about more advanced usage and a section on what is needed to set up your own BASE server. The information is current as of BASE version 1.2.17b, which was released on November 6, 2005.

Animals↗

PubMed2005

Random maps and attractors in random Boolean networks.

Despite their apparent simplicity, random Boolean networks display a rich variety of dynamical behaviors. Much work has been focused on the properties and abundance of attractors. The topologies of random Boolean networks with one input per node can be seen as graphs of random maps. We introduce an approach to investigating random maps and finding analytical results for attractors in random Boolean networks with the corresponding topology. Approximating some other non-chaotic networks to be of this class, we apply the analytic results to them. For this approximation, we observe a strikingly good agreement on the numbers of attractors of various lengths. We also investigate observables related to the average number of attractors in relation to the typical number of attractors. Here, we find strong differences that highlight the difficulties in making direct comparisons between random Boolean networks and real systems. Furthermore, we demonstrate the power of our approach by deriving some results for random maps. These results include the distribution of the number of components in random maps, along with asymptotic expansions for cumulants up to the fourth order.

Journal Article↗

PubMed2005

Signal transduction pathway profiling of individual tumor samples.

BACKGROUND: Signal transduction pathways convey information from the outside of the cell to transcription factors, which in turn regulate gene expression. Our objective is to analyze tumor gene expression data from microarrays in the context of such pathways. RESULTS: We use pathways compiled from the TRANSPATH/TRANSFAC databases and the literature, and three publicly available cancer microarray data sets. Variation in pathway activity, across the samples, is gauged by the degree of correlation between downstream targets of a pathway. Two correlation scores are applied; one considers all pairs of downstream targets, and the other considers only pairs without common transcription factors. Several pathways are found to be differentially active in the data sets using these scores. Moreover, we devise a score for pathway activity in individual samples, based on the average expression value of the downstream targets. Statistical significance is assigned to the scores using permutation of genes as null model. Hence, for individual samples, the status of a pathway is given as a sign, + or -, and a p-value. This approach defines a projection of high-dimensional gene expression data onto low-dimensional pathway activity scores. For each dataset and many pathways we find a much larger number of significant samples than expected by chance. Finally, we find that several sample-wise pathway activities are significantly associated with clinical classifications of the samples. CONCLUSION: This study shows that it is feasible to infer signal transduction pathway activity, in individual samples, from gene expression data. Furthermore, these pathway activities are biologically relevant in the three cancer data sets.

Breast Neoplasms↗

PubMed2004

Genetic networks with canalyzing Boolean rules are always stable.

We determine stability and attractor properties of random Boolean genetic network models with canalyzing rules for a variety of architectures. For all power law, exponential, and flat in-degree distributions, we find that the networks are dynamically stable. Furthermore, for architectures with few inputs per node, the dynamics of the networks is close to critical. In addition, the fraction of genes that are active decreases with the number of inputs per node. These results are based upon investigating ensembles of networks using analytical methods. Also, for different in-degree distributions, the numbers of fixed points and cycles are calculated, with results intuitively consistent with stability analysis; fewer inputs per node implies more cycles, and vice versa. There are hints that genetic networks acquire broader degree distributions with evolution, and hence our results indicate that for single cells, the dynamics should become more stable with evolution. However, such an effect is very likely compensated for by multicellular dynamics, because one expects less stability when interactions among cells are included. We verify this by simulations of a simple model for interactions among cells.

Animals↗

PubMed2003

Random Boolean network models and the yeast transcriptional network.

The recently measured yeast transcriptional network is analyzed in terms of simplified Boolean network models, with the aim of determining feasible rule structures, given the requirement of stable solutions of the generated Boolean networks. We find that, for ensembles of generated models, those with canalyzing Boolean rules are remarkably stable, whereas those with random Boolean rules are only marginally stable. Furthermore, substantial parts of the generated networks are frozen, in the sense that they reach the same state, regardless of initial state. Thus, our ensemble approach suggests that the yeast network shows highly ordered dynamics.

Computational Biology↗

PubMed2003

Superpolynomial growth in the number of attractors in Kauffman networks.

The Kauffman model describes a particularly simple class of random Boolean networks. Despite the simplicity of the model, it exhibits complex behavior and has been suggested as a model for real world network problems. We introduce a novel approach to analyzing attractors in random Boolean networks, and applying it to Kauffman networks we prove that the average number of attractors grows faster than any power law with system size.

Internet↗

PubMed2002

BioArray Software Environment (BASE): a platform for comprehensive management and analysis of microarray data.

The microarray technique requires the organization and analysis of vast amounts of data. These data include information about the samples hybridized, the hybridization images and their extracted data matrices, and information about the physical array, the features and reporter molecules. We present a web-based customizable bioinformatics solution called BioArray Software Environment (BASE) for the management and analysis of all areas of microarray experimentation. All software necessary to run a local server is freely available.

Database Management Systems↗