8,715 research outputs found
A stochastic model dissects cell states in biological transition processes
Many biological processes, including differentiation, reprogramming, and disease transformations, involve transitions of cells through distinct states. Direct, unbiased investigation of cell states and their transitions is challenging due to several factors, including limitations of single-cell assays. Here we present a stochastic model of cellular transitions that allows underlying single-cell information, including cell-state-specific parameters and rates governing transitions between states, to be estimated from genome-wide, population-averaged time-course data. The key novelty of our approach lies in specifying latent stochastic models at the single-cell level, and then aggregating these models to give a likelihood that links parameters at the single-cell level to observables at the population level. We apply our approach in the context of reprogramming to pluripotency. This yields new insights, including profiles of two intermediate cell states, that are supported by independent single-cell studies. Our model provides a general conceptual framework for the study of cell transitions, including epigenetic transformations
Potential conservation of circadian clock proteins in the phylum Nematoda as revealed by bioinformatic searches
Although several circadian rhythms have been described in C. elegans, its molecular clock remains elusive. In this work we employed a novel bioinformatic approach, applying probabilistic methodologies, to search for circadian clock proteins of several of the best studied circadian model organisms of different taxa (Mus musculus, Drosophila melanogaster, Neurospora crassa, Arabidopsis thaliana and Synechoccocus elongatus) in the proteomes of C. elegans and other members of the phylum Nematoda. With this approach we found that the Nematoda contain proteins most related to the core and accessory proteins of the insect and mammalian clocks, which provide new insights into the nematode clock and the evolution of the circadian system.Fil: Romanowski, AndrĂ©s. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Parque Centenario. Instituto de Investigaciones BioquĂmicas de Buenos Aires. FundaciĂłn Instituto Leloir. Instituto de Investigaciones BioquĂmicas de Buenos Aires; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂa. Laboratorio de CronobiologĂa; ArgentinaFil: Garavaglia, MatĂas Javier. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂa. Laboratorio de Ing.genĂ©tica y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Goya, MarĂa Eugenia. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂa. Laboratorio de CronobiologĂa; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Ghiringhelli, Pablo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂa. Laboratorio de Ing.genĂ©tica y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Golombek, Diego Andres. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂa. Laboratorio de CronobiologĂa; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentin
A continuum model of transcriptional bursting
Transcription occurs in stochastic bursts. Early models based upon RNA hybridisation studies suggest bursting dynamics arise from alternating inactive and permissive states. Here we investigate bursting mechanism in live cells by quantitative imaging of actin gene transcription, combined with molecular genetics, stochastic simulation and probabilistic modelling. In contrast to early models, our data indicate a continuum of transcriptional states, with a slowly fluctuating initiation rate converting the gene between different levels of activity, interspersed with extended periods of inactivity. We place an upper limit of 40s on the lifetime of fluctuations in elongation rate, with initiation rate variations persisting an order of magnitude longer. TATA mutations reduce the accessibility of high activity states, leaving the lifetime of on- and off-states unchanged. A continuum or spectrum of gene states potentially enables a wide dynamic range for cell responses to stimuli
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
The EM Algorithm and the Rise of Computational Biology
In the past decade computational biology has grown from a cottage industry
with a handful of researchers to an attractive interdisciplinary field,
catching the attention and imagination of many quantitatively-minded
scientists. Of interest to us is the key role played by the EM algorithm during
this transformation. We survey the use of the EM algorithm in a few important
computational biology problems surrounding the "central dogma"; of molecular
biology: from DNA to RNA and then to proteins. Topics of this article include
sequence motif discovery, protein sequence alignment, population genetics,
evolutionary models and mRNA expression microarray data analysis.Comment: Published in at http://dx.doi.org/10.1214/09-STS312 the Statistical
Science (http://www.imstat.org/sts/) by the Institute of Mathematical
Statistics (http://www.imstat.org
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