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Search Results: 1 - 10 of 186111 matches for " Michael B Eisen "
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All motifs are NOT created equal: structural properties of transcription factor-DNA interactions and the inference of sequence specificity
Michael B Eisen
Genome Biology , 2005, DOI: 10.1186/gb-2005-6-5-p7
Identifying Cis-Regulatory Sequences by Word Profile Similarity
Garmay Leung, Michael B. Eisen
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006901
Abstract: Background Recognizing regulatory sequences in genomes is a continuing challenge, despite a wealth of available genomic data and a growing number of experimentally validated examples. Methodology/Principal Findings We discuss here a simple approach to search for regulatory sequences based on the compositional similarity of genomic regions and known cis-regulatory sequences. This method, which is not limited to searching for predefined motifs, recovers sequences known to be under similar regulatory control. The words shared by the recovered sequences often correspond to known binding sites. Furthermore, we show that although local word profile clustering is predictive for the regulatory sequences involved in blastoderm segmentation, local dissimilarity is a more universal feature of known regulatory sequences in Drosophila. Conclusions/Significance Our method leverages sequence motifs within a known regulatory sequence to identify co-regulated sequences without explicitly defining binding sites. We also show that regulatory sequences can be distinguished from surrounding sequences by local sequence dissimilarity, a novel feature in identifying regulatory sequences across a genome. Source code for WPH-finder is available for download at http://rana.lbl.gov/downloads/wph.tar.gz.
Design of a combinatorial DNA microarray for protein-DNA interaction studies
Julian Mintseris, Michael B Eisen
BMC Bioinformatics , 2006, DOI: 10.1186/1471-2105-7-429
Abstract: Here we present an algorithmic approach to experimental design of a microarray that allows for testing full specificity of a transcription factor binding to all possible DNA binding sites of a given length, with optimally efficient use of the array. This design is universal, works for any factor that binds a sequence motif and is not species-specific. Furthermore, simulation results show that data produced with the designed arrays is easier to analyze and would result in more precise identification of binding sites.In this study, we present a design of a double stranded DNA microarray for protein-DNA interaction studies and show that our algorithm allows optimally efficient use of the arrays for this purpose. We believe such a design will prove useful for transcription factor binding site identification and other biological problems.With the human and many other genome sequences complete or nearing completion, we are approaching the goal of identifying all the protein coding genes. However, to understand the function of these genes in different physiological contexts, it is important to understand how their expression is regulated. Mechanisms of gene regulation are varied and complex and unraveling them will require a combination of approaches[1,2]. Having a catalog of all the transcription factors and being able to characterize their binding specificity at cis-regulatory sites would provide a fruitful starting point.Recent advances in chromatin immunoprecipitation (CHIP) methods have led to large-scale efforts to determine all protein-DNA binding events in yeast[3,4] but scaling up such methods for mammalian genomes may prove difficult. Protein-binding microarrays (PBM), initially developed on a small scale by Bulyk et al[5,6] showed promise in identifying transcription factor binding specificity with high accuracy and was recently successfully scaled up for the yeast genome by using PBMs with all known yeast intergenic regions[7]. Although an exciting advance in t
Silent but Not Static: Accelerated Base-Pair Substitution in Silenced Chromatin of Budding Yeasts
Leonid Teytelman,Michael B. Eisen,Jasper Rine
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000247
Abstract: Subtelomeric DNA in budding yeasts, like metazoan heterochromatin, is gene poor, repetitive, transiently silenced, and highly dynamic. The rapid evolution of subtelomeric regions is commonly thought to arise from transposon activity and increased recombination between repetitive elements. However, we found evidence of an additional factor in this diversification. We observed a surprising level of nucleotide divergence in transcriptionally silenced regions in inter-species comparisons of Saccharomyces yeasts. Likewise, intra-species analysis of polymorphisms also revealed increased SNP frequencies in both intergenic and synonymous coding positions of silenced DNA. This analysis suggested that silenced DNA in Saccharomyces cerevisiae and closely related species had increased single base-pair substitution that was likely due to the effects of the silencing machinery on DNA replication or repair.
Evolutionary Mirages: Selection on Binding Site Composition Creates the Illusion of Conserved Grammars in Drosophila Enhancers
Richard W. Lusk,Michael B. Eisen
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000829
Abstract: The clustering of transcription factor binding sites in developmental enhancers and the apparent preferential conservation of clustered sites have been widely interpreted as proof that spatially constrained physical interactions between transcription factors are required for regulatory function. However, we show here that selection on the composition of enhancers alone, and not their internal structure, leads to the accumulation of clustered sites with evolutionary dynamics that suggest they are preferentially conserved. We simulated the evolution of idealized enhancers from Drosophila melanogaster constrained to contain only a minimum number of binding sites for one or more factors. Under this constraint, mutations that destroy an existing binding site are tolerated only if a compensating site has emerged elsewhere in the enhancer. Overlapping sites, such as those frequently observed for the activator Bicoid and repressor Krüppel, had significantly longer evolutionary half-lives than isolated sites for the same factors. This leads to a substantially higher density of overlapping sites than expected by chance and the appearance that such sites are preferentially conserved. Because D. melanogaster (like many other species) has a bias for deletions over insertions, sites tended to become closer together over time, leading to an overall clustering of sites in the absence of any selection for clustered sites. Since this effect is strongest for the oldest sites, clustered sites also incorrectly appear to be preferentially conserved. Following speciation, sites tend to be closer together in all descendent species than in their common ancestors, violating the common assumption that shared features of species' genomes reflect their ancestral state. Finally, we show that selection on binding site composition alone recapitulates the observed number of overlapping and closely neighboring sites in real D. melanogaster enhancers. Thus, this study calls into question the common practice of inferring “cis-regulatory grammars” from the organization and evolutionary dynamics of developmental enhancers.
Exploring the conditional coregulation of yeast gene expression through fuzzy k-means clustering
Audrey P Gasch, Michael B Eisen
Genome Biology , 2002, DOI: 10.1186/gb-2002-3-11-research0059
Abstract: We used a heuristically modified version of fuzzy k-means clustering to identify overlapping clusters of yeast genes based on published gene-expression data following the response of yeast cells to environmental changes. We have validated the method by identifying groups of functionally related and coregulated genes, and in the process we have uncovered new correlations between yeast genes and between the experimental conditions based on similarities in gene-expression patterns. To investigate the regulation of gene expression, we correlated the clusters with known transcription factor binding sites present in the genes' promoters. These results give insights into the mechanism of the regulation of gene expression in yeast cells responding to environmental changes.Fuzzy k-means clustering is a useful analytical tool for extracting biological insights from gene-expression data. Our analysis presented here suggests that a prevalent theme in the regulation of yeast gene expression is the condition-specific coregulation of overlapping sets of genes.All organisms possess an essentially fixed repertoire of proteins determined by their genome sequence. They have evolved to survive varying internal and external environments by carefully controlling the abundance and activity of these proteins to suit their conditions. To simplify this task, genes whose products function together are often under common regulatory control such that they are coordinately expressed under the appropriate conditions. This property has been frequently exploited in the analysis of genome-wide expression data, as the experimental observation that a set of genes is coexpressed frequently implies that the genes share a biological function and are under common regulatory control [1]. Many proteins have multiple roles in the cell, however, and act with distinct sets of cooperating proteins to fulfill each role. Their genes are therefore coexpressed with different groups of genes, each governed by a dist
GATA: a graphic alignment tool for comparative sequence analysis
David A Nix, Michael B Eisen
BMC Bioinformatics , 2005, DOI: 10.1186/1471-2105-6-9
Abstract: To address some of these issues, we created a stand alone, platform independent, graphic alignment tool for comparative sequence analysis (GATA http://gata.sourceforge.net/ webcite). GATA uses the NCBI-BLASTN program and extensive post-processing to identify all small sub-alignments above a low cut-off score. These are graphed as two shaded boxes, one for each sequence, connected by a line using the coordinate system of their parent sequence. Shading and colour are used to indicate score and orientation. A variety of options exist for querying, modifying and retrieving conserved sequence elements. Extensive gene annotation can be added to both sequences using a standardized General Feature Format (GFF) file.GATA uses the NCBI-BLASTN program in conjunction with post-processing to exhaustively align two DNA sequences. It provides researchers with a fine-grained alignment and visualization tool aptly suited for non-coding, 0–200 kb, pairwise, sequence analysis. It functions independent of sequence feature ordering or orientation, and readily visualizes both large and small sequence inversions, duplications, and segment shuffling. Since the alignment is visual and does not contain gaps, gene annotation can be added to both sequences to create a thoroughly descriptive picture of DNA conservation that is well suited for comparative sequence analysis.The most widely used methods for aligning DNA sequences rely on dynamic programming algorithms initially developed by Smith-Waterman and Needleman-Wunsch [1,2]. These algorithms create the mathematically best possible alignment of two sequences by inserting gaps in either sequence to maximize the score of base pair matches and minimize penalties for base pair mismatches and sequence gaps. Although these methods have proven invaluable in understanding sequence conservation and gene relatedness, they make several assumptions. One of their assumptions in generating the "best" alignment is that sequence features are collinear. For
Improving transcriptome assembly through error correction of high-throughput sequence reads
Matthew D. MacManes,Michael B. Eisen
PeerJ , 2013, DOI: 10.7717/peerj.113
Abstract: The study of functional genomics, particularly in non-model organisms, has been dramatically improved over the last few years by the use of transcriptomes and RNAseq. While these studies are potentially extremely powerful, a computationally intensive procedure, the de novo construction of a reference transcriptome must be completed as a prerequisite to further analyses. The accurate reference is critically important as all downstream steps, including estimating transcript abundance are critically dependent on the construction of an accurate reference. Though a substantial amount of research has been done on assembly, only recently have the pre-assembly procedures been studied in detail. Specifically, several stand-alone error correction modules have been reported on and, while they have shown to be effective in reducing errors at the level of sequencing reads, how error correction impacts assembly accuracy is largely unknown. Here, we show via use of a simulated and empiric dataset, that applying error correction to sequencing reads has significant positive effects on assembly accuracy, and should be applied to all datasets. A complete collection of commands which will allow for the production of Reptile corrected reads is available at https://github.com/macmanes/error_correction/tree/master/scripts and as File S1.
Sequencing mRNA from Cryo-Sliced Drosophila Embryos to Determine Genome-Wide Spatial Patterns of Gene Expression
Peter A. Combs, Michael B. Eisen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071820
Abstract: Complex spatial and temporal patterns of gene expression underlie embryo differentiation, yet methods do not yet exist for the efficient genome-wide determination of spatial expression patterns during development. In situ imaging of transcripts and proteins is the gold-standard, but it is difficult and time consuming to apply to an entire genome, even when highly automated. Sequencing, in contrast, is fast and genome-wide, but is generally applied to homogenized tissues, thereby discarding spatial information. To take advantage of the efficiency and comprehensiveness of sequencing while retaining spatial information, we cryosectioned individual blastoderm stage Drosophila melanogaster embryos along the anterior-posterior axis and developed methods to reliably sequence the mRNA isolated from each 25 μm slice. The spatial patterns of gene expression we infer closely match patterns previously determined by in situ hybridization and microscopy. We applied this method to generate a genome-wide timecourse of spatial gene expression from shortly after fertilization through gastrulation. We identified numerous genes with spatial patterns that have not yet been described in the several ongoing systematic in situ based projects. This simple experiment demonstrates the potential for combining careful anatomical dissection with high-throughput sequencing to obtain spatially resolved gene expression on a genome-wide scale.
Drosophila Embryogenesis Scales Uniformly across Temperature in Developmentally Diverse Species
Steven G. Kuntz ,Michael B. Eisen
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004293
Abstract: Temperature affects both the timing and outcome of animal development, but the detailed effects of temperature on the progress of early development have been poorly characterized. To determine the impact of temperature on the order and timing of events during Drosophila melanogaster embryogenesis, we used time-lapse imaging to track the progress of embryos from shortly after egg laying through hatching at seven precisely maintained temperatures between 17.5°C and 32.5°C. We employed a combination of automated and manual annotation to determine when 36 milestones occurred in each embryo. D. melanogaster embryogenesis takes 33 hours at 17.5°C, and accelerates with increasing temperature to a low of 16 hours at 27.5°C, above which embryogenesis slows slightly. Remarkably, while the total time of embryogenesis varies over two fold, the relative timing of events from cellularization through hatching is constant across temperatures. To further explore the relationship between temperature and embryogenesis, we expanded our analysis to cover ten additional Drosophila species of varying climatic origins. Six of these species, like D. melanogaster, are of tropical origin, and embryogenesis time at different temperatures was similar for them all. D. mojavensis, a sub-tropical fly, develops slower than the tropical species at lower temperatures, while D. virilis, a temperate fly, exhibits slower development at all temperatures. The alpine sister species D. persimilis and D. pseudoobscura develop as rapidly as tropical flies at cooler temperatures, but exhibit diminished acceleration above 22.5°C and have drastically slowed development by 30°C. Despite ranging from 13 hours for D. erecta at 30°C to 46 hours for D. virilis at 17.5°C, the relative timing of events from cellularization through hatching is constant across all species and temperatures examined here, suggesting the existence of a previously unrecognized timer controlling the progress of embryogenesis that has been tuned by natural selection as each species diverges.
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