78 research outputs found
Single cell analyses of ES cells reveal alternative pluripotent cell states and molecular mechanisms that control self-renewal
No full textAnalyses of gene expression in single mouse embryonic stem cells (mESCs) cultured in serum and LIF revealed the presence of two distinct cell subpopulations with individual gene expression signatures. Comparisons with published data revealed that cells in the first subpopulation are phenotypically similar to cells isolated from the inner cell mass (ICM). In contrast, cells in the second subpopulation appear to be more mature. Pluripotency Gene Regulatory Network (PGRN) reconstruction based on single-cell data and published data suggested antagonistic roles for Oct4 and Nanog in the maintenance of pluripotency states. Integrated analyses of published genomic binding (ChIP) data strongly supported this observation. Certain target genes alternatively regulated by OCT4 and NANOG, such as Sall4 and Zscan10, feed back into the top hierarchical regulator Oct4. Analyses of such incoherent feedforward loops with feedback (iFFL-FB) suggest a dynamic model for the maintenance of mESC pluripotency and self-renewal
ClusterDraw web server: a tool to identify and visualize clusters of binding motifs for transcription factors
No full textTemporal waves of coherent gene expression during <i>Drosophila</i> embryogenesis
No full textAbstract
Motivation: Animal development depends on localized patterns of gene expression. Whole-genome methods permit the global identification of differential expression patterns. However, most gene-expression-clustering methods focus on the analysis of entire expression profiles, rather than temporal segments or time windows.
Results: In the current study, local clustering of temporal time windows was applied to developing embryos of the fruitfly, Drosophila melanogaster. Large-scale developmental events, involving temporal activation of hundreds of genes, were identified as discrete gene clusters. The time-duration analysis revealed six temporal waves of coherent gene expression during Drosophila embryogenesis. The most powerful expression waves preceded major morphogenetic movements, such as germ band elongation and dorsal closure. These waves of gene expression coincide with the inhibition of maternal transcripts during early development, the specification of ectoderm, differentiation of the nervous system, differentiation of the digestive tract, deposition of the larval cuticle and the reorganization of the cytoskeleton during global morphogenetic events. We discuss the implications of these findings with respect to the gene regulatory networks governing Drosophila development.
Availability: Data and software are available from the UC Berkeley web resource http://flydev.berkeley.edu/cgi-bin/GTEM/dmap_dm-ag/index_dmap.htm
Contact: [email protected]
Supplementary information: Supplementary data are available at Bioinformatics online.</jats:p
Time warping of evolutionary distant temporal gene expression data based on noise suppression
No full textAbstract Background Comparative analysis of genome wide temporal gene expression data has a broad potential area of application, including evolutionary biology, developmental biology, and medicine. However, at large evolutionary distances, the construction of global alignments and the consequent comparison of the time-series data are difficult. The main reason is the accumulation of variability in expression profiles of orthologous genes, in the course of evolution. Results We applied Pearson distance matrices, in combination with other noise-suppression techniques and data filtering to improve alignments. This novel framework enhanced the capacity to capture the similarities between the temporal gene expression datasets separated by large evolutionary distances. We aligned and compared the temporal gene expression data in budding (Saccharomyces cerevisiae) and fission (Schizosaccharomyces pombe) yeast, which are separated by more then ~400 myr of evolution. We found that the global alignment (time warping) properly matched the duration of cell cycle phases in these distant organisms, which was measured in prior studies. At the same time, when applied to individual ortholog pairs, this alignment procedure revealed groups of genes with distinct alignments, different from the global alignment. Conclusion Our alignment-based predictions of differences in the cell cycle phases between the two yeast species were in a good agreement with the existing data, thus supporting the computational strategy adopted in this study. We propose that the existence of the alternative alignments, specific to distinct groups of genes, suggests presence of different synchronization modes between the two organisms and possible functional decoupling of particular physiological gene networks in the course of evolution.</p
The Drosophila gap gene network is composed of two parallel toggle switches.
No full textDrosophila "gap" genes provide the first response to maternal gradients in the early fly embryo. Gap genes are expressed in a series of broad bands across the embryo during first hours of development. The gene network controlling the gap gene expression patterns includes inputs from maternal gradients and mutual repression between the gap genes themselves. In this study we propose a modular design for the gap gene network, involving two relatively independent network domains. The core of each network domain includes a toggle switch corresponding to a pair of mutually repressive gap genes, operated in space by maternal inputs. The toggle switches present in the gap network are evocative of the phage lambda switch, but they are operated positionally (in space) by the maternal gradients, so the synthesis rates for the competing components change along the embryo anterior-posterior axis. Dynamic model, constructed based on the proposed principle, with elements of fractional site occupancy, required 5-7 parameters to fit quantitative spatial expression data for gap gradients. The identified model solutions (parameter combinations) reproduced major dynamic features of the gap gradient system and explained gap expression in a variety of segmentation mutants
A rationale for the enhanceosome and other evolutionarily constrained enhancers
No full textSummaryMetazoan enhancers direct localized stripes, bands and cell-specific patterns of gene expression during development (for example [1]). A typical enhancer is a 500 base pair DNA segment that contains clustered binding sites for two or more sequence-specific transcription factors. Roughly half of all enhancers are located somewhere in the 5′ flanking region of the associated transcription unit, while the other half are distributed among introns, 3′ flanking regions or even protein-coding sequences (for example [2]). Bioinformatics studies suggest that enhancers usually contain a flexible arrangement of binding sites (for example [3]). Here, we present a model to explain why a special subset of enhancers contains a fixed organization
Enhancer responses to similarly distributed antagonistic gradients in development.
No full textFormation of spatial gene expression patterns in development depends on transcriptional responses mediated by gene control regions, enhancers. Here, we explore possible responses of enhancers to overlapping gradients of antagonistic transcriptional regulators in the Drosophila embryo. Using quantitative models based on enhancer structure, we demonstrate how a pair of antagonistic transcription factor gradients with similar or even identical spatial distributions can lead to the formation of distinct gene expression domains along the embryo axes. The described mechanisms are sufficient to explain the formation of the anterior and the posterior knirps expression, the posterior hunchback expression domain, and the lateral stripes of rhomboid expression and of other ventral neurogenic ectodermal genes. The considered principles of interaction between antagonistic gradients at the enhancer level can also be applied to diverse developmental processes, such as domain specification in imaginal discs, or even eyespot pattern formation in the butterfly wing
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