Developmental roles of 21 Drosophila transcription factors are determined by quantitative differences in binding to an overlapping set of thousands of genomic regions
TL;DR: It is suggested that most animal transcription factors will be found to show a similar broad overlapping pattern of binding in vivo, with specificity achieved by modulating the amount, rather than the identity, of bound factor.
Abstract: We previously established that six sequence-specific transcription factors that initiate anterior/posterior patterning in Drosophila bind to overlapping sets of thousands of genomic regions in blastoderm embryos. While regions bound at high levels include known and probable functional targets, more poorly bound regions are preferentially associated with housekeeping genes and/or genes not transcribed in the blastoderm, and are frequently found in protein coding sequences or in less conserved non-coding DNA, suggesting that many are likely non-functional. Here we show that an additional 15 transcription factors that regulate other aspects of embryo patterning show a similar quantitative continuum of function and binding to thousands of genomic regions in vivo. Collectively, the 21 regulators show a surprisingly high overlap in the regions they bind given that they belong to 11 DNA binding domain families, specify distinct developmental fates, and can act via different cis-regulatory modules. We demonstrate, however, that quantitative differences in relative levels of binding to shared targets correlate with the known biological and transcriptional regulatory specificities of these factors. It is likely that the overlap in binding of biochemically and functionally unrelated transcription factors arises from the high concentrations of these proteins in nuclei, which, coupled with their broad DNA binding specificities, directs them to regions of open chromatin. We suggest that most animal transcription factors will be found to show a similar broad overlapping pattern of binding in vivo, with specificity achieved by modulating the amount, rather than the identity, of bound factor.
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TL;DR: It is demonstrated in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B cell lineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions.
9,620 citations
Cites background from "Developmental roles of 21 Drosophil..."
...This model offers an explanation for the extensive genome-wide and cell typespecific colocalization of transcription factors observed in various previous studies (Chen et al., 2008; MacArthur et al., 2009) and provides insights into how simple combinations of lineage-restricted transcription factors on a genome-wide scale can specify promoter-distal cis-regulatory elements ultimately responsible for both cell identity and cell type-specific responses to diverse signaling inputs....
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...…for the extensive genome-wide and cell typespecific colocalization of transcription factors observed in various previous studies (Chen et al., 2008; MacArthur et al., 2009) and provides insights into how simple combinations of lineage-restricted transcription factors on a genome-wide scale can…...
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...Comparisons of the genome-wide binding patterns of different transcription factors in a variety of species and cell types have generated two major insights regarding transcription factor binding patterns: (1) different factors in the same cell type tend to colocalize on a genome-wide scale (Chen et al., 2008; MacArthur et al., 2009), and (2) the same factor in different cell types or at different stages of development exhibits different genome-wide binding patterns (Lupien et al....
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...…transcription factor binding patterns: (1) different factors in the same cell type tend to colocalize on a genome-wide scale (Chen et al., 2008; MacArthur et al., 2009), and (2) the same factor in different cell types or at different stages of development exhibits different genome-wide binding…...
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TL;DR: Current knowledge of transcription factor function from genomic and genetic studies is reviewed and how different strategies, including extensive cooperative regulation, progressive priming of regulatory elements, and the integration of activities from multiple enhancers, confer specificity and robustness to transcriptional regulation during development are discussed.
Abstract: Developmental progression is driven by specific spatiotemporal domains of gene expression, which give rise to stereotypically patterned embryos even in the presence of environmental and genetic variation. Views of how transcription factors regulate gene expression are changing owing to recent genome-wide studies of transcription factor binding and RNA expression. Such studies reveal patterns that, at first glance, seem to contrast with the robustness of the developmental processes they encode. Here, we review our current knowledge of transcription factor function from genomic and genetic studies and discuss how different strategies, including extensive cooperative regulation (both direct and indirect), progressive priming of regulatory elements, and the integration of activities from multiple enhancers, confer specificity and robustness to transcriptional regulation during development.
1,774 citations
TL;DR: The field is reviewed and how pioneer factors may enable cellular reprogramming is described, which can passively enhance transcription by reducing the number of additional factors that are needed to bind the DNA, culminating in activation.
Abstract: Transcription factors are adaptor molecules that detect regulatory sequences in the DNA and target the assembly of protein complexes that control gene expression. Yet much of the DNA in the eukaryotic cell is in nucleosomes and thereby occluded by histones, and can be further occluded by higher-order chromatin structures and repressor complexes. Indeed, genome-wide location analyses have revealed that, for all transcription factors tested, the vast majority of potential DNA-binding sites are unoccupied, demonstrating the inaccessibility of most of the nuclear DNA. This raises the question of how target sites at silent genes become bound de novo by transcription factors, thereby initiating regulatory events in chromatin. Binding cooperativity can be sufficient for many kinds of factors to simultaneously engage a target site in chromatin and activate gene expression. However, in cases in which the binding of a series of factors is sequential in time and thus not initially cooperative, special "pioneer transcription factors" can be the first to engage target sites in chromatin. Such initial binding can passively enhance transcription by reducing the number of additional factors that are needed to bind the DNA, culminating in activation. In addition, pioneer factor binding can actively open up the local chromatin and directly make it competent for other factors to bind. Passive and active roles for the pioneer factor FoxA occur in embryonic development, steroid hormone induction, and human cancers. Herein we review the field and describe how pioneer factors may enable cellular reprogramming.
1,452 citations
Broad Institute1, Harvard University2, University of Chicago3, Duke University4, Lawrence Berkeley National Laboratory5, Massachusetts Institute of Technology6, Ontario Institute for Cancer Research7, University of Florida8, University of Liège9, Memorial Sloan Kettering Cancer Center10, Utrecht University11, University of Cambridge12, National Institutes of Health13, University of California, Berkeley14, Cold Spring Harbor Laboratory15, University of Connecticut16, Washington University in St. Louis17, Affymetrix18, Indiana University19, University of California, Santa Cruz20, Rutgers University21, University of California, San Diego22, Fred Hutchinson Cancer Research Center23
TL;DR: The Drosophila Encyclopedia of DNA Elements (modENCODE) project as mentioned in this paper has been used to map transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines.
Abstract: To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.
1,102 citations
Journal Article•
TL;DR: Two studies identified regions of the nematode and fly genomes that show highly occupied targets (or HOT) regions where DNA was bound by more than 15 of the transcription factors analyzed and the expression of related genes were characterized.
1,052 citations
References
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TL;DR: The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing.
Abstract: Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
35,225 citations
TL;DR: WebLogo generates sequence logos, graphical representations of the patterns within a multiple sequence alignment that provide a richer and more precise description of sequence similarity than consensus sequences and can rapidly reveal significant features of the alignment otherwise difficult to perceive.
Abstract: WebLogo generates sequence logos, graphical representations of the patterns within a multiple sequence alignment. Sequence logos provide a richer and more precise description of sequence similarity than consensus sequences and can rapidly reveal significant features of the alignment otherwise difficult to perceive. Each logo consists of stacks of letters, one stack for each position in the sequence. The overall height of each stack indicates the sequence conservation at that position (measured in bits), whereas the height of symbols within the stack reflects the relative frequency of the corresponding amino or nucleic acid at that position. WebLogo has been enhanced recently with additional features and options, to provide a convenient and highly configurable sequence logo generator. A command line interface and the complete, open WebLogo source code are available for local installation and customization.
10,721 citations
Ewan Birney, John A. Stamatoyannopoulos1, Anindya Dutta2, Roderic Guigó3 +317 more•Institutions (44)
TL;DR: Functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project are reported, providing convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts.
Abstract: We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
5,091 citations
TL;DR: Insight is provided into the transcriptional regulation of stem cells and how OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal and how they collaborate to form regulatory circuitry consisting of autoregulatory and feedforward loops.
4,447 citations
TL;DR: The phenotypes of the mutant embryos indicate that the process of segmentation involves at least three levels of spatial organization: the entire egg as developmental unit, a repeat unit with the length of two segments, and the individual segment.
Abstract: In systematic searches for embryonic lethal mutants of Drosophila melanogaster we have identified 15 loci which when mutated alter the segmental pattern of the larva. These loci probably represent the majority of such genes in Drosophila. The phenotypes of the mutant embryos indicate that the process of segmentation involves at least three levels of spatial organization: the entire egg as developmental unit, a repeat unit with the length of two segments, and the individual segment.
4,170 citations
"Developmental roles of 21 Drosophil..." refers background in this paper
...Only 40 to 50 sequence-specific regulators provide the spatial and temporal patterning information to the network, making it particularly tractable for system-wide analyses [13-15]....
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