9,442 research outputs found
Using temporal correlation in factor analysis for reconstructing transcription factor activities
Two-level gene regulatory networks consist of the transcription factors (TFs) in the top level and their regulated genes in the second level. The expression profiles of the regulated genes are the observed high-throughput data given by experiments such as microarrays. The activity profiles of the TFs are treated as hidden variables as well as the connectivity matrix that indicates the regulatory relationships of TFs with their regulated genes. Factor analysis (FA) as well as other methods, such as the network component algorithm, has been suggested for reconstructing gene regulatory networks and also for predicting TF activities. They have been applied to E. coli and yeast data with the assumption that these datasets consist of identical and independently distributed samples. Thus, the main drawback of these algorithms is that they ignore any time correlation existing within the TF profiles. In this paper, we extend previously studied FA algorithms to include time correlation within the transcription factors. At the same time, we consider connectivity matrices that are sparse in order to capture the existing sparsity present in gene regulatory networks. The TFs activity profiles obtained by this approach are significantly smoother than profiles from previous FA algorithms. The periodicities in profiles from yeast expression data become prominent in our reconstruction. Moreover, the strength of the correlation between time points is estimated and can be used to assess the suitability of the experimental time interval
Spatial clustering and common regulatory elements correlate with coordinated gene expression
Many cellular responses to surrounding cues require temporally concerted
transcriptional regulation of multiple genes. In prokaryotic cells, a
single-input-module motif with one transcription factor regulating multiple
target genes can generate coordinated gene expression. In eukaryotic cells,
transcriptional activity of a gene is affected by not only transcription
factors but also the epigenetic modifications and three-dimensional chromosome
structure of the gene. To examine how local gene environment and transcription
factor regulation are coupled, we performed a combined analysis of time-course
RNA-seq data of TGF-\b{eta} treated MCF10A cells and related epigenomic and
Hi-C data. Using Dynamic Regulatory Events Miner (DREM), we clustered
differentially expressed genes based on gene expression profiles and associated
transcription factors. Genes in each class have similar temporal gene
expression patterns and share common transcription factors. Next, we defined a
set of linear and radial distribution functions, as used in statistical
physics, to measure the distributions of genes within a class both spatially
and linearly along the genomic sequence. Remarkably, genes within the same
class despite sometimes being separated by tens of million bases (Mb) along
genomic sequence show a significantly higher tendency to be spatially close
despite sometimes being separated by tens of Mb along the genomic sequence than
those belonging to different classes do. Analyses extended to the process of
mouse nervous system development arrived at similar conclusions. Future studies
will be able to test whether this spatial organization of chromosomes
contributes to concerted gene expression.Comment: 30 pages, 9 figures, accepted in PLoS Computational Biolog
Sparse regulatory networks
In many organisms the expression levels of each gene are controlled by the
activation levels of known "Transcription Factors" (TF). A problem of
considerable interest is that of estimating the "Transcription Regulation
Networks" (TRN) relating the TFs and genes. While the expression levels of
genes can be observed, the activation levels of the corresponding TFs are
usually unknown, greatly increasing the difficulty of the problem. Based on
previous experimental work, it is often the case that partial information about
the TRN is available. For example, certain TFs may be known to regulate a given
gene or in other cases a connection may be predicted with a certain
probability. In general, the biology of the problem indicates there will be
very few connections between TFs and genes. Several methods have been proposed
for estimating TRNs. However, they all suffer from problems such as unrealistic
assumptions about prior knowledge of the network structure or computational
limitations. We propose a new approach that can directly utilize prior
information about the network structure in conjunction with observed gene
expression data to estimate the TRN. Our approach uses penalties on the
network to ensure a sparse structure. This has the advantage of being
computationally efficient as well as making many fewer assumptions about the
network structure. We use our methodology to construct the TRN for E. coli and
show that the estimate is biologically sensible and compares favorably with
previous estimates.Comment: Published in at http://dx.doi.org/10.1214/10-AOAS350 the Annals of
Applied Statistics (http://www.imstat.org/aoas/) by the Institute of
Mathematical Statistics (http://www.imstat.org
Reconstruction of metabolic networks from high-throughput metabolite profiling data: in silico analysis of red blood cell metabolism
We investigate the ability of algorithms developed for reverse engineering of
transcriptional regulatory networks to reconstruct metabolic networks from
high-throughput metabolite profiling data. For this, we generate synthetic
metabolic profiles for benchmarking purposes based on a well-established model
for red blood cell metabolism. A variety of data sets is generated, accounting
for different properties of real metabolic networks, such as experimental
noise, metabolite correlations, and temporal dynamics. These data sets are made
available online. We apply ARACNE, a mainstream transcriptional networks
reverse engineering algorithm, to these data sets and observe performance
comparable to that obtained in the transcriptional domain, for which the
algorithm was originally designed.Comment: 14 pages, 3 figures. Presented at the DIMACS Workshop on Dialogue on
Reverse Engineering Assessment and Methods (DREAM), Sep 200
Mathematical modelling plant signalling networks
During the last two decades, molecular genetic studies and the completion of the sequencing of the Arabidopsis thaliana genome have increased knowledge of hormonal regulation in plants. These signal transduction pathways act in concert through gene regulatory and signalling networks whose main components have begun to be elucidated. Our understanding of the resulting cellular processes is hindered by the complex, and sometimes counter-intuitive, dynamics of the networks, which may be interconnected through feedback controls and cross-regulation. Mathematical modelling provides a valuable tool to investigate such dynamics and to perform in silico experiments that may not be easily carried out in a laboratory. In this article, we firstly review general methods for modelling gene and signalling networks and their application in plants. We then describe specific models of hormonal perception and cross-talk in plants. This sub-cellular analysis paves the way for more comprehensive mathematical studies of hormonal transport and signalling in a multi-scale setting
Mathematical and computational modelling of post-transcriptional gene relation by micro-RNA
Mathematical models and computational simulations have proved valuable in many areas of cell biology, including gene regulatory networks. When properly calibrated against experimental data, kinetic models can be used to describe how the concentrations of key species evolve over time. A reliable model allows ‘what if’ scenarios to be investigated quantitatively in silico, and also provides a means to compare competing hypotheses about the underlying biological mechanisms at work. Moreover, models at different scales of resolution can be merged into a bigger picture ‘systems’ level description. In the case where gene regulation is post-transcriptionally affected by microRNAs, biological understanding and experimental techniques have only recently matured to the extent that we can postulate and test kinetic models. In this chapter, we summarize some recent work that takes the first steps towards realistic modelling, focusing on the contributions of the authors. Using a deterministic ordinary differential equation framework, we derive models from first principles and test them for consistency with recent experimental data, including microarray and mass spectrometry measurements. We first consider typical mis-expression experiments, where the microRNA level is instantaneously boosted or depleted and thereafter remains at a fixed level. We then move on to a more general setting where the microRNA is simply treated as another species in the reaction network, with microRNA-mRNA binding forming the basis for the post-transcriptional repression. We include some speculative comments about the potential for kinetic modelling to contribute to the more widespread sequence and network based approaches in the qualitative investigation of microRNA based gene regulation. We also consider what new combinations of experimental data will be needed in order to make sense of the increased systems-level complexity introduced by microRNAs
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