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Author

Aaron Hechmer

Other affiliations: University of Victoria
Bio: Aaron Hechmer is an academic researcher from Lawrence Berkeley National Laboratory. The author has contributed to research in topics: Blastoderm & Gene. The author has an hindex of 4, co-authored 5 publications receiving 1085 citations. Previous affiliations of Aaron Hechmer include University of Victoria.

Papers
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Journal ArticleDOI
TL;DR: Surprisingly, for five of the six factors, their recognition sites are not unambiguously more constrained evolutionarily than the immediate flanking DNA, even in more highly bound and presumably functional regions, indicating that comparative DNA sequence analysis is limited in its ability to identify functional transcription factor targets.
Abstract: Identifying the genomic regions bound by sequence-specific regulatory factors is central both to deciphering the complex DNA cis-regulatory code that controls transcription in metazoans and to determining the range of genes that shape animal morphogenesis. We used whole-genome tiling arrays to map sequences bound in Drosophila melanogaster embryos by the six maternal and gap transcription factors that initiate anterior–posterior patterning. We find that these sequence-specific DNA binding proteins bind with quantitatively different specificities to highly overlapping sets of several thousand genomic regions in blastoderm embryos. Specific high- and moderate-affinity in vitro recognition sequences for each factor are enriched in bound regions. This enrichment, however, is not sufficient to explain the pattern of binding in vivo and varies in a context-dependent manner, demonstrating that higher-order rules must govern targeting of transcription factors. The more highly bound regions include all of the over 40 well-characterized enhancers known to respond to these factors as well as several hundred putative new cis-regulatory modules clustered near developmental regulators and other genes with patterned expression at this stage of embryogenesis. The new targets include most of the microRNAs (miRNAs) transcribed in the blastoderm, as well as all major zygotically transcribed dorsal–ventral patterning genes, whose expression we show to be quantitatively modulated by anterior–posterior factors. In addition to these highly bound regions, there are several thousand regions that are reproducibly bound at lower levels. However, these poorly bound regions are, collectively, far more distant from genes transcribed in the blastoderm than highly bound regions; are preferentially found in protein-coding sequences; and are less conserved than highly bound regions. Together these observations suggest that many of these poorly bound regions are not involved in early-embryonic transcriptional regulation, and a significant proportion may be nonfunctional. Surprisingly, for five of the six factors, their recognition sites are not unambiguously more constrained evolutionarily than the immediate flanking DNA, even in more highly bound and presumably functional regions, indicating that comparative DNA sequence analysis is limited in its ability to identify functional transcription factor targets.

517 citations

Journal ArticleDOI
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.

367 citations

Journal ArticleDOI
TL;DR: In this article, a genome-wide location analysis (chromatin immunoprecipitation-microarray chip [ChIP-chip] analysis) revealed that NELF is concentrated at the 5′ ends of 2,111 genes in Drosophila cells.
Abstract: Recent analyses of RNA polymerase II (Pol II) revealed that Pol II is concentrated at the promoters of many active and inactive genes. NELF causes Pol II to pause in the promoter-proximal region of the hsp70 gene in Drosophila melanogaster. In this study, genome-wide location analysis (chromatin immunoprecipitation-microarray chip [ChIP-chip] analysis) revealed that NELF is concentrated at the 5′ ends of 2,111 genes in Drosophila cells. Permanganate genomic footprinting was used to determine if paused Pol II colocalized with NELF. Forty-six of 56 genes with NELF were found to have paused Pol II. Pol II pauses 30 to 50 nucleotides downstream from transcription start sites. Analysis of DNA sequences in the vicinity of paused Pol II identified a conserved DNA sequence that probably associates with TFIID but detected no evidence of RNA secondary structures or other conserved sequences that might directly control elongation. ChIP-chip experiments indicate that GAGA factor associates with 39% of the genes that have NELF. Surprisingly, NELF associates with almost one-half of the most highly expressed genes, indicating that NELF is not necessarily a repressor of gene expression. NELF-associated pausing of Pol II might be an obligatory but sometimes transient checkpoint during the transcription cycle.

235 citations

Proceedings ArticleDOI
27 Oct 2006
TL;DR: The design challenge with LogoRhythms was to create a forgiving text based API that allows the neophyte programmer to explore programming and low-level digital audio manipulations.
Abstract: Teaching computer music presents opportunities and challenges at both secondary and university levels by bringing together students with widely varying exposures to and interests for mathematics and computer programming. Visual languages like MAX/MSP are popular with many musicians, but the idiom doesn't necessarily transfer well to a text language such as Java or C++, languages that might be used in a wider variety of programming problems. Our design challenge with LogoRhythms was to create a forgiving text based API that allows the neophyte programmer to explore programming and low-level digital audio manipulations. Since any musical composition is essentially a novel program, the opportunity for custom software is endless and the programming task given as a creative endeavor. LogoRhythms encourages functional style programming. Examples are provided showing lists and higher order functions used to create simple harmonies and melodies with a discussion of how to balance abstracting elegance with "abstracting elusiveness."

6 citations

Journal ArticleDOI
TL;DR: The corrected version of the Table below gives the intended information for the enzyme phosphorylated at the C terminus, which is recognized by the H14 monoclonal antibody.
Abstract: Correction for: Li Xy, MacArthur S, Bourgon R, Nix D, Pollard DA, et al. (2008) Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm. PLoS Biol 6(2): e27. doi:10.1371/journal.pbio.0060027 The information in Table 1 for RNA polymerase II was incorrectly given for the form of the enzyme unphosphorylated at the C-terminal tail, which is recognized by the 8WG16 monoclonal antibody. The corrected version of the Table below gives the intended information for the enzyme phosphorylated at the C terminus, which is recognized by the H14 monoclonal antibody. Table 1 Number of Regions Bound by Transcription Factors

3 citations


Cited by
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Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
TL;DR: How properties of enhancer sequences and chromatin are used to predict enhancers in genome-wide studies are discussed and recently developed high-throughput methods that allow the direct testing and identification of enhancers on the basis of their activity are covered.
Abstract: Cellular development, morphology and function are governed by precise patterns of gene expression. These are established by the coordinated action of genomic regulatory elements known as enhancers or cis-regulatory modules. More than 30 years after the initial discovery of enhancers, many of their properties have been elucidated; however, despite major efforts, we only have an incomplete picture of enhancers in animal genomes. In this Review, we discuss how properties of enhancer sequences and chromatin are used to predict enhancers in genome-wide studies. We also cover recently developed high-throughput methods that allow the direct testing and identification of enhancers on the basis of their activity. Finally, we discuss recent technological advances and current challenges in the field of regulatory genomics.

1,163 citations

Journal ArticleDOI
Sushmita Roy1, Jason Ernst1, Peter V. Kharchenko2, Pouya Kheradpour1, Nicolas Nègre3, Matthew L. Eaton4, Jane M. Landolin5, Christopher A. Bristow1, Lijia Ma3, Michael F. Lin1, Stefan Washietl6, Bradley I. Arshinoff7, Ferhat Ay8, Patrick E. Meyer9, Nicolas Robine10, Nicole L. Washington5, Luisa Di Stefano2, Eugene Berezikov11, Christopher D. Brown3, Rogerio Candeias6, Joseph W. Carlson5, Adrian Carr12, Irwin Jungreis1, Daniel Marbach1, Rachel Sealfon1, Michael Y. Tolstorukov2, Sebastian Will6, Artyom A. Alekseyenko2, Carlo G. Artieri13, Benjamin W. Booth5, Angela N. Brooks14, Qi Dai10, Carrie A. Davis15, Michael O. Duff16, X. Feng, Andrey A. Gorchakov2, Tingting Gu17, Jorja G. Henikoff10, Philipp Kapranov18, Renhua Li13, Heather K. MacAlpine4, John H. Malone13, Aki Minoda5, Jared T. Nordman6, Katsutomo Okamura10, Marc D. Perry7, Sara K. Powell4, Nicole C. Riddle17, Akiko Sakai2, Anastasia Samsonova2, Jeremy E. Sandler5, Yuri B. Schwartz2, Noa Sher6, Rebecca Spokony3, David Sturgill13, Marijke J. van Baren17, Kenneth H. Wan5, Li Yang16, Charles Yu5, Elise A. Feingold13, Peter J. Good13, Mark S. Guyer13, Rebecca F. Lowdon13, Kami Ahmad2, Justen Andrews19, Bonnie Berger1, Steven E. Brenner14, Michael R. Brent17, Lucy Cherbas19, Sarah C. R. Elgin17, Thomas R. Gingeras18, Robert L. Grossman3, Roger A. Hoskins5, Thomas C. Kaufman19, W. J. Kent20, Mitzi I. Kuroda2, Terry L. Orr-Weaver6, Norbert Perrimon2, Vincenzo Pirrotta21, James W. Posakony22, Bing Ren22, Steven Russell12, Peter Cherbas19, Brenton R. Graveley16, Suzanna E. Lewis5, Gos Micklem12, Brian Oliver13, Peter J. Park2, Susan E. Celniker5, Steven Henikoff23, Gary H. Karpen14, Eric C. Lai10, David M. MacAlpine4, Lincoln Stein7, Kevin P. White3, Manolis Kellis1 
24 Dec 2010-Science
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