Friday, June 28, 2013

A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern in Human Adipose Tissue

A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern in Human Adipose Tissue:
by Tina Rönn, Petr Volkov, Cajsa Davegårdh, Tasnim Dayeh, Elin Hall, Anders H. Olsson, Emma Nilsson, Åsa Tornberg, Marloes Dekker Nitert, Karl-Fredrik Eriksson, Helena A. Jones, Leif Groop, Charlotte Ling

Epigenetic mechanisms are implicated in gene regulation and the development of different diseases. The epigenome differs between cell types and has until now only been characterized for a few human tissues. Environmental factors potentially alter the epigenome. Here we describe the genome-wide pattern of DNA methylation in human adipose tissue from 23 healthy men, with a previous low level of physical activity, before and after a six months exercise intervention. We also investigate the differences in adipose tissue DNA methylation between 31 individuals with or without a family history of type 2 diabetes. DNA methylation was analyzed using Infinium HumanMethylation450 BeadChip, an array containing 485,577 probes covering 99% RefSeq genes. Global DNA methylation changed and 17,975 individual CpG sites in 7,663 unique genes showed altered levels of DNA methylation after the exercise intervention (q<0.05). Differential mRNA expression was present in 1/3 of gene regions with altered DNA methylation, including RALBP1, HDAC4 and NCOR2 (q<0.05). Using a luciferase assay, we could show that increased DNA methylation in vitro of the RALBP1 promoter suppressed the transcriptional activity (p = 0.03). Moreover, 18 obesity and 21 type 2 diabetes candidate genes had CpG sites with differences in adipose tissue DNA methylation in response to exercise (q<0.05), including TCF7L2 (6 CpG sites) and KCNQ1 (10 CpG sites). A simultaneous change in mRNA expression was seen for 6 of those genes. To understand if genes that exhibit differential DNA methylation and mRNA expression in human adipose tissue in vivo affect adipocyte metabolism, we silenced Hdac4 and Ncor2 respectively in 3T3-L1 adipocytes, which resulted in increased lipogenesis both in the basal and insulin stimulated state. In conclusion, exercise induces genome-wide changes in DNA methylation in human adipose tissue, potentially affecting adipocyte metabolism.

Heritable Change Caused by Transient Transcription Errors

Heritable Change Caused by Transient Transcription Errors:
by Alasdair J. E. Gordon, Dominik Satory, Jennifer A. Halliday, Christophe Herman

Transmission of cellular identity relies on the faithful transfer of information from the mother to the daughter cell. This process includes accurate replication of the DNA, but also the correct propagation of regulatory programs responsible for cellular identity. Errors in DNA replication (mutations) and protein conformation (prions) can trigger stable phenotypic changes and cause human disease, yet the ability of transient transcriptional errors to produce heritable phenotypic change (‘epimutations’) remains an open question. Here, we demonstrate that transcriptional errors made specifically in the mRNA encoding a transcription factor can promote heritable phenotypic change by reprogramming a transcriptional network, without altering DNA. We have harnessed the classical bistable switch in the lac operon, a memory-module, to capture the consequences of transient transcription errors in living Escherichia coli cells. We engineered an error-prone transcription sequence (A9 run) in the gene encoding the lac repressor and show that this ‘slippery’ sequence directly increases epigenetic switching, not mutation in the cell population. Therefore, one altered transcript within a multi-generational series of many error-free transcripts can cause long-term phenotypic consequences. Thus, like DNA mutations, transcriptional epimutations can instigate heritable changes that increase phenotypic diversity, which drives both evolution and disease.

Drosophila Distal-less and Rotund Bind a Single Enhancer Ensuring Reliable and Robust bric-a-brac2 Expression in Distinct Limb Morphogenetic Fields

Drosophila Distal-less and Rotund Bind a Single Enhancer Ensuring Reliable and Robust bric-a-brac2 Expression in Distinct Limb Morphogenetic Fields:
by Aissette Baanannou, Luis Humberto Mojica-Vazquez, Gaylord Darras, Jean-Louis Couderc, David L. Cribbs, Muriel Boube, Henri-Marc Bourbon



Most identified Drosophila appendage-patterning genes encode DNA-binding proteins, whose cross-regulatory interactions remain to be better characterized at the molecular level, notably by studying their direct binding to tissue-specific transcriptional enhancers. A fine-tuned spatio-temporal expression of bric-a-brac2 (bab2) along concentric rings is essential for proper proximo-distal (P-D) differentiation of legs and antennae. However, within the genetic interaction landscape governing limb development, no transcription factor directly controlling bab2 expression has been identified to date. Using site-targeted GFP reporter assay and BAC recombineering, we show here that restricted bab2 expression in leg and antennal imaginal discs relies on a single 567-bp-long cis-regulatory module (CRM), termed LAE (for leg and antennal enhancer). We show that this CRM (i) is necessary and sufficient to ensure normal bab2 activity in developing leg and antenna, and (ii) is structurally and functionally conserved among Drosophilidae. Through deletion and site-directed mutagenesis approaches, we identified within the LAE essential sequence motifs required in both leg and antennal tissues. Using genetic and biochemical tests, we establish that in the LAE (i) a key TAAT-rich activator motif interacts with the homeodomain P-D protein Distal-less (Dll) and (ii) a single T-rich activator motif binds the C2H2 zinc-finger P-D protein Rotund (Rn), leading to bab2 up-regulation respectively in all or specifically in the proximal-most ring(s), both in leg and antenna. Joint ectopic expression of Dll and Rn is sufficient to cell-autonomously activate endogenous bab2 and LAE-driven reporter expression in wing and haltere cells. Our findings indicate that accuracy, reliability and robustness of developmental gene expression do not necessarily require cis-regulatory information redundancy.

OpenSpinMicroscopy: an open-source integrated microscopy platform

OpenSpinMicroscopy: an open-source integrated microscopy platform:
Nature Methods 10, 599 (2013).
doi:10.1038/nmeth.2508

Authors: Emilio J Gualda, Tiago Vale, Pedro Almada, José A Feijó, Gabriel G Martins & Nuno Moreno

OpenSPIM: an open-access light-sheet microscopy platform

OpenSPIM: an open-access light-sheet microscopy platform:
Nature Methods 10, 598 (2013).
doi:10.1038/nmeth.2507

Authors: Peter G Pitrone, Johannes Schindelin, Luke Stuyvenberg, Stephan Preibisch, Michael Weber, Kevin W Eliceiri, Jan Huisken & Pavel Tomancak

Genetic and Neural Mechanisms that Inhibit Drosophila from Mating with Other Species

Genetic and Neural Mechanisms that Inhibit Drosophila from Mating with Other Species: Pu Fan, Devanand S. Manoli, Osama M. Ahmed, Yi Chen, Neha Agarwal, Sara Kwong, Allen G. Cai, Jeffrey Neitz, Adam Renslo, Bruce S. Baker, Nirao M. Shah. Genetically hard-wired neural mechanisms must enforce behavioral reproductive isolation because interspecies courtship is rare even in sexually naïve animals of most species. We find that the chem....

Thursday, June 27, 2013

Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription

Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription:
Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription

Nature 498, 7455 (2013). doi:10.1038/nature12209

Authors: Michael T. Y. Lam, Han Cho, Hanna P. Lesch, David Gosselin, Sven Heinz, Yumiko Tanaka-Oishi, Christopher Benner, Minna U. Kaikkonen, Aneeza S. Kim, Mika Kosaka, Cindy Y. Lee, Andy Watt, Tamar R. Grossman, Michael G. Rosenfeld, Ronald M. Evans & Christopher K. Glass



Rev-Erb-α and Rev-Erb-β are nuclear receptors that regulate the expression of genes involved in the control of circadian rhythm, metabolism and inflammatory responses. Rev-Erbs function as transcriptional repressors by recruiting nuclear receptor co-repressor (NCoR)–HDAC3 complexes to Rev-Erb response elements in enhancers and promoters of target genes, but the molecular basis for cell-specific programs of repression is not known. Here we present evidence that in mouse macrophages Rev-Erbs regulate target gene expression by inhibiting the functions of distal enhancers that are selected by macrophage-lineage-determining factors, thereby establishing a macrophage-specific program of repression. Remarkably, the repressive functions of Rev-Erbs are associated with their ability to inhibit the transcription of enhancer-derived RNAs (eRNAs). Furthermore, targeted degradation of eRNAs at two enhancers subject to negative regulation by Rev-Erbs resulted in reduced expression of nearby messenger RNAs, suggesting a direct role of these eRNAs in enhancer function. By precisely defining eRNA start sites using a modified form of global run-on sequencing that quantifies nascent 5′ ends, we show that transfer of full enhancer activity to a target promoter requires both the sequences mediating transcription-factor binding and the specific sequences encoding the eRNA transcript. These studies provide evidence for a direct role of eRNAs in contributing to enhancer functions and suggest that Rev-Erbs act to suppress gene expression at a distance by repressing eRNA transcription.

Temporal patterning of Drosophila medulla neuroblasts controls neural fates

Temporal patterning of Drosophila medulla neuroblasts controls neural fates:
Temporal patterning of Drosophila medulla neuroblasts controls neural fates

Nature 498, 7455 (2013). doi:10.1038/nature12319

Authors: Xin Li, Ted Erclik, Claire Bertet, Zhenqing Chen, Roumen Voutev, Srinidhi Venkatesh, Javier Morante, Arzu Celik & Claude Desplan
In the Drosophila optic lobes, the medulla processes visual information coming from inner photoreceptors R7 and R8 and from lamina neurons. It contains approximately 40,000 neurons belonging to more than 70 different types. Here we describe how precise temporal patterning of neural progenitors generates

Combinatorial temporal patterning in progenitors expands neural diversity

Combinatorial temporal patterning in progenitors expands neural diversity:
Combinatorial temporal patterning in progenitors expands neural diversity

Nature 498, 7455 (2013). doi:10.1038/nature12266

Authors: Omer Ali Bayraktar & Chris Q. Doe



Human outer subventricular zone (OSVZ) neural progenitors and Drosophila type II neuroblasts both generate intermediate neural progenitors (INPs) that populate the adult cerebral cortex or central complex, respectively. It is unknown whether INPs simply expand or also diversify neural cell types. Here we show that

Intact cluster and chordate-like expression of ParaHox genes in a sea star

Intact cluster and chordate-like expression of ParaHox genes in a sea star: Background:
The ParaHox genes are thought to be major players in patterning the gut of several bilaterian taxa. Though this is a fundamental role that these transcription factors play, their activities are not limited to the endoderm and extend to both ectodermal and mesodermal tissues. Three genes compose the ParaHox group: Gsx, Xlox and Cdx. In some taxa (mostly chordates but to some degree also in protostomes) the three genes are arranged into a genomic cluster, in a similar fashion to what has been shown for the better-known Hox genes. Sea urchins possess the full complement of ParaHox genes but they are all dispersed throughout the genome, an arrangement that, perhaps, represented the primitive condition for all echinoderms. In order to understand the evolutionary history of this group of genes we cloned and characterized all ParaHox genes, studied their expression patterns and identified their genomic loci in a member of an earlier branching group of echinoderms, the asteroid Patiria miniata.
Results:
We identified the three ParaHox orthologues in the genome of Patiria miniata. While one of them, PmGsx is provided as maternal message, with no zygotic activation afterwards, the other two, PmLox and PmCdx are expressed during embryogenesis, within restricted domains of both endoderm and ectoderm. Screening of a Patiria BAC library led to the identification of a clone containing the three genes. The transcriptional directions of PmGsx and PmLox are opposed to that of the PmCdx gene within the cluster.
Conclusions:
The identification of Patiria miniata ParaHox genes has revealed the fact that these genes are clustered in the genome, in contrast to what has been reported for echinoids. Since the presence of an intact cluster, or at least a partial cluster, has been reported in chordates and polychaetes respectively, it becomes clear that within echinoderms, sea urchins have modified the original bilaterian arrangement. Moreover, the sea star ParaHox domains of expression show chordate-like features not found in the sea urchin, confirming that the dynamics of gene expression for the respective genes and their putative regulatory interactions have clearly changed over evolutionary time within the echinoid lineage.

Wednesday, June 26, 2013

DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape

DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape:
Nature Genetics 45, 836 (2013).


 
doi:10.1038/ng.2649

Authors: Mingchao Xie, Chibo Hong, Bo Zhang, Rebecca F Lowdon, Xiaoyun Xing, Daofeng Li, Xin Zhou, Hyung Joo Lee, Cecile L Maire, Keith L Ligon, Philippe Gascard, Mahvash Sigaroudinia, Thea D Tlsty, Theresa Kadlecek, Arthur Weiss, Henriette O'Geen, Peggy J Farnham, Pamela A F Madden, Andrew J Mungall, Angela Tam, Baljit Kamoh, Stephanie Cho, Richard Moore, Martin Hirst, Marco A Marra, Joseph F Costello & Ting Wang
Transposable element (TE)-derived sequences comprise half of the human genome and DNA methylome and are presumed to be densely methylated and inactive. Examination of genome-wide DNA methylation status within 928 TE subfamilies in human embryonic and adult tissues identified unexpected tissue-specific and subfamily-specific hypomethylation signatures. Genes proximal to tissue-specific hypomethylated TE sequences were enriched for functions important for the relevant tissue type, and their expression correlated strongly with hypomethylation within the TEs. When hypomethylated, these TE sequences gained tissue-specific enhancer marks, including monomethylation of histone H3 at lysine 4 (H3K4me1) and occupancy by p300, and a majority exhibited enhancer activity in reporter gene assays. Many such TEs also harbored binding sites for transcription factors that are important for tissue-specific functions and showed evidence of evolutionary selection. These data suggest that sequences derived from TEs may be responsible for wiring tissue type–specific regulatory networks and may have acquired tissue-specific epigenetic regulation.

Genome-wide inference of natural selection on human transcription factor binding sites

Genome-wide inference of natural selection on human transcription factor binding sites:
Nature Genetics 45, 723 (2013).


 
doi:10.1038/ng.2658

Authors: Leonardo Arbiza, Ilan Gronau, Bulent A Aksoy, Melissa J Hubisz, Brad Gulko, Alon Keinan & Adam Siepel

Tuesday, June 25, 2013

Key ornamental innovations and diversification [Evolution]

Key ornamental innovations and diversification [Evolution]: Patterns of biodiversity are often explained by ecological processes, where traits that promote novel ways of interacting with the environment (key innovations) play a fundamental role in promoting diversification. However, sexual selection and social competition can also promote diversification through rapid evolution of ornamental traits. Because selection can operate only...

cis-regulatory change in snake evolution [Evolution]

cis-regulatory change in snake evolution [Evolution]: A goal of evolutionary developmental biology is to understand the genetic changes, and subsequent changes in developmental programs, which underlie body plan evolution. In PNAS, Guerreiro et al. (1) characterize genetic variation that likely contributes to the homogenization of the vertebral column in snakes. The authors identify a polymorphism in...

Sunday, June 23, 2013

Ancient cis-regulatory constraints and the evolution of genome architecture

Ancient cis-regulatory constraints and the evolution of genome architecture: Manuel Irimia, Ignacio Maeso, Scott W. Roy, Hunter B. Fraser.



  • Conserved gene order reveals constraints on cis-regulation and genome architecture.
  • Hundreds of local gene associations have been conserved since the origin of animals.
  • Constraints include coregulation and the formation of multigenic regulatory blocks.
  • Establishment and disruption of regulatory blocks are highly dynamic in evolution.
  • No conserved regulatory blocks have been found so far in non-animal eukaryotes.

Cohesin and Polycomb Proteins Functionally Interact to Control Transcription at Silenced and Active Genes

Cohesin and Polycomb Proteins Functionally Interact to Control Transcription at Silenced and Active Genes:
by Cheri A. Schaaf, Ziva Misulovin, Maria Gause, Amanda Koenig, David W. Gohara, Audrey Watson, Dale Dorsett

Cohesin is crucial for proper chromosome segregation but also regulates gene transcription and organism development by poorly understood mechanisms. Using genome-wide assays in Drosophila developing wings and cultured cells, we find that cohesin functionally interacts with Polycomb group (PcG) silencing proteins at both silenced and active genes. Cohesin unexpectedly facilitates binding of Polycomb Repressive Complex 1 (PRC1) to many active genes, but their binding is mutually antagonistic at silenced genes. PRC1 depletion decreases phosphorylated RNA polymerase II and mRNA at many active genes but increases them at silenced genes. Depletion of cohesin reduces long-range interactions between Polycomb Response Elements in the invected-engrailed gene complex where it represses transcription. These studies reveal a previously unrecognized role for PRC1 in facilitating productive gene transcription and provide new insights into how cohesin and PRC1 control development.

Transcription-Factor-Mediated DNA Looping Probed by High-Resolution, Single-Molecule Imaging in Live E. coli Cells

Transcription-Factor-Mediated DNA Looping Probed by High-Resolution, Single-Molecule Imaging in Live E. coli Cells:
by Zach Hensel, Xiaoli Weng, Arvin Cesar Lagda, Jie Xiao



DNA looping mediated by transcription factors plays critical roles in prokaryotic gene regulation. The “genetic switch” of bacteriophage λ determines whether a prophage stays incorporated in the E. coli chromosome or enters the lytic cycle of phage propagation and cell lysis. Past studies have shown that long-range DNA interactions between the operator sequences OR and OL (separated by 2.3 kb), mediated by the λ repressor CI (accession number P03034), play key roles in regulating the λ switch. In vitro, it was demonstrated that DNA segments harboring the operator sequences formed loops in the presence of CI, but CI-mediated DNA looping has not been directly visualized in vivo, hindering a deep understanding of the corresponding dynamics in realistic cellular environments. We report a high-resolution, single-molecule imaging method to probe CI-mediated DNA looping in live E. coli cells. We labeled two DNA loci with differently colored fluorescent fusion proteins and tracked their separations in real time with ∼40 nm accuracy, enabling the first direct analysis of transcription-factor-mediated DNA looping in live cells. Combining looping measurements with measurements of CI expression levels in different operator mutants, we show quantitatively that DNA looping activates transcription and enhances repression. Further, we estimated the upper bound of the rate of conformational change from the unlooped to the looped state, and discuss how chromosome compaction may impact looping kinetics. Our results provide insights into transcription-factor-mediated DNA looping in a variety of operator and CI mutant backgrounds in vivo, and our methodology can be applied to a broad range of questions regarding chromosome conformations in prokaryotes and higher organisms.

A combinatorial regulatory signature controls terminal differentiation of the dopaminergic nervous system in C. elegans [Research Papers]

A combinatorial regulatory signature controls terminal differentiation of the dopaminergic nervous system in C. elegans [Research Papers]:
Terminal differentiation programs in the nervous system are encoded by cis-regulatory elements that control the expression of terminal features of individual neuron types. We decoded the regulatory information that controls the expression of five enzymes and transporters that define the terminal identity of all eight dopaminergic neurons in the nervous system of the Caenorhabditis elegans hermaphrodite. We show that the tightly coordinated, robust expression of these dopaminergic enzymes and transporters ("dopamine pathway") is ensured through a combinatorial cis-regulatory signature that is shared by all dopamine pathway genes. This signature is composed of an Ets domain-binding site, recognized by the previously described AST-1 Ets domain factor, and two distinct types of homeodomain-binding sites that act in a partially redundant manner. Through genetic screens, we identified the sole C. elegans Distalless/Dlx ortholog, ceh-43, as a factor that acts through one of the homeodomain sites to control both induction and maintenance of terminal dopaminergic fate. The second type of homeodomain site is a Pbx-type site, which is recognized in a partially redundant and neuron subtype-specific manner by two Pbx factors, ceh-20 and ceh-40, revealing novel roles of Pbx factors in the context of terminal neuron differentiation. Taken together, we revealed a specific regulatory signature and cognate, terminal selector-type transcription factors that define the entire dopaminergic nervous system of an animal. Dopaminergic neurons in the mouse olfactory bulb express a similar combinatorial transcription factor collective of Ets/Dlx/Pbx factors, suggesting deep phylogenetic conservation of dopaminergic regulatory programs.

A double take on bivalent promoters [Reviews]

A double take on bivalent promoters [Reviews]:
Histone modifications and chromatin-associated protein complexes are crucially involved in the control of gene expression, supervising cell fate decisions and differentiation. Many promoters in embryonic stem (ES) cells harbor a distinctive histone modification signature that combines the activating histone H3 Lys 4 trimethylation (H3K4me3) mark and the repressive H3K27me3 mark. These bivalent domains are considered to poise expression of developmental genes, allowing timely activation while maintaining repression in the absence of differentiation signals. Recent advances shed light on the establishment and function of bivalent domains; however, their role in development remains controversial, not least because suitable genetic models to probe their function in developing organisms are missing. Here, we explore avenues to and from bivalency and propose that bivalent domains and associated chromatin-modifying complexes safeguard proper and robust differentiation.

Cell-Type-Specific Profiling of Gene Expression and Chromatin Binding without Cell Isolation: Assaying RNA Pol II Occupancy in Neural Stem Cells

Cell-Type-Specific Profiling of Gene Expression and Chromatin Binding without Cell Isolation: Assaying RNA Pol II Occupancy in Neural Stem Cells: Tony D. Southall, Katrina S. Gold, Boris Egger, Catherine M. Davidson, Elizabeth E. Caygill, Owen J. Marshall, Andrea H. Brand.



Cell-type-specific transcriptional profiling often requires the isolation of specific cell types from complex tissues. We have developed “TaDa,” a technique that enables cell-specific profiling wi....

Saturday, June 22, 2013

Evolutionary History and Ecological Processes Shape a Local Multilevel Antagonistic Network

Evolutionary History and Ecological Processes Shape a Local Multilevel Antagonistic Network: Marianne Elias, Colin Fontaine, F.J. Frank van Veen.



Uncovering the processes that shape the architecture of interaction networks is a major challenge in ecology. Studies have consistently revealed that more closely related taxa tend to show greater....

Predicting C4 Photosynthesis Evolution: Modular, Individually Adaptive Steps on a Mount Fuji Fitness Landscape

Predicting C4 Photosynthesis Evolution: Modular, Individually Adaptive Steps on a Mount Fuji Fitness Landscape: David Heckmann, Stefanie Schulze, Alisandra Denton, Udo Gowik, Peter Westhoff, Andreas P.M. Weber, Martin J. Lercher. An ultimate goal of evolutionary biology is the prediction and experimental verification of adaptive trajectories on macroevolutionary timescales. This aim has rarely been achieved for complex bio....

Horizontal Gene Transfer from Diverse Bacteria to an Insect Genome Enables a Tripartite Nested Mealybug Symbiosis

Horizontal Gene Transfer from Diverse Bacteria to an Insect Genome Enables a Tripartite Nested Mealybug Symbiosis: Filip Husnik, Naruo Nikoh, Ryuichi Koga, Laura Ross, Rebecca P. Duncan, Manabu Fujie, Makiko Tanaka, Nori Satoh, Doris Bachtrog, Alex C.C. Wilson, Carol D. von Dohlen, Takema Fukatsu, John P. McCutcheon.



The smallest reported bacterial genome belongs to Tremblaya princeps, a symbiont of Planococcus citri mealybugs (PCIT). Tremblaya PCIT not only has a 139 kb genome, but posses....

Tuesday, June 18, 2013

Transcriptional interpretation of ERK signaling [Systems Biology]

Transcriptional interpretation of ERK signaling [Systems Biology]: ERK controls gene expression in development, but mechanisms that link ERK activation to changes in transcription are not well understood. We used high-resolution analysis of signaling dynamics to study transcriptional interpretation of ERK signaling during Drosophila embryogenesis, at a stage when ERK induces transcription of intermediate neuroblasts defective (ind), a...

piggyBac transposase tools for genome engineering [Genetics]

piggyBac transposase tools for genome engineering [Genetics]: The transposon piggyBac is being used increasingly for genetic studies. Here, we describe modified versions of piggyBac transposase that have potentially wide-ranging applications, such as reversible transgenesis and modified targeting of insertions. piggyBac is distinguished by its ability to excise precisely, restoring the donor site to its pretransposon state. This...

Crossing the Species Barrier: Genomic Hotspots of Introgression between Two Highly Divergent Ciona intestinalis Species

Crossing the Species Barrier: Genomic Hotspots of Introgression between Two Highly Divergent Ciona intestinalis Species:
Inferring a realistic demographic model from genetic data is an important challenge to gain insights into the historical events during the speciation process and to detect molecular signatures of selection along genomes. Recent advances in divergence population genetics have reported that speciation in face of gene flow occurred more frequently than theoretically expected, but the approaches used did not account for genome-wide heterogeneity (GWH) in introgression rates. Here, we investigate the impact of GWH on the inference of divergence with gene flow between two cryptic species of the marine model Ciona intestinalis by analyzing polymorphism and divergence patterns in 852 protein-coding sequence loci. These morphologically similar entities are highly diverged molecular-wise, but evidence of hybridization has been reported in both laboratory and field studies. We compare various speciation models and test for GWH under the approximate Bayesian computation framework. Our results demonstrate the presence of significant extents of gene flow resulting from a recent secondary contact after >3 My of divergence in isolation. The inferred rates of introgression are relatively low, highly variable across loci and mostly unidirectional, which is consistent with the idea that numerous genetic incompatibilities have accumulated over time throughout the genomes of these highly diverged species. A genomic map of the level of gene flow identified two hotspots of introgression, that is, large genome regions of unidirectional introgression. This study clarifies the history and degree of isolation of two cryptic and partially sympatric model species and provides a methodological framework to investigate GWH at various stages of speciation process.

Evolution of the Eye Transcriptome under Constant Darkness in Sinocyclocheilus Cavefish

Evolution of the Eye Transcriptome under Constant Darkness in Sinocyclocheilus Cavefish:
In adaptating to perpetual darkness, cave species gradually lose eyes and body pigmentation and evolve alternatives for exploring their environments. Although troglodyte features evolved independently many times in cavefish, we do not yet know whether independent evolution of these characters involves common genetic mechanisms. Surface-dwelling and many cave-dwelling species make the freshwater teleost genus Sinocyclocheilus an excellent model for studying the evolution of adaptations to life in constant darkness. We compared the mature retinal histology of surface and cave species in Sinocyclocheilus and found that adult cavefish showed a reduction in the number and length of photoreceptor cells. To identify genes and genetic pathways that evolved in constant darkness, we used RNA-seq to compare eyes of surface and cave species. De novo transcriptome assemblies were developed for both species, and contigs were annotated with gene ontology. Results from cave-dwelling Sinocyclocheilus revealed reduced transcription of phototransduction and other genes important for retinal function. In contrast to the blind Mexican tetra cavefish Astyanax mexicanus, our results on morphologies and gene expression suggest that evolved retinal reduction in cave-dwelling Sinocyclocheilus occurs in a lens-independent fashion by the reduced proliferation and downregulation of transcriptional factors shown to have direct roles in retinal development and maintenance, including cone-rod homeobox (crx) and Wnt pathway members. These results show that the independent evolution of retinal degeneration in cavefish can occur by different developmental genetic mechanisms.

Multiple Genomic Changes Associated with Reorganization of Gene Regulation and Adaptation in Yeast

Multiple Genomic Changes Associated with Reorganization of Gene Regulation and Adaptation in Yeast:
Frequently during evolution, new phenotypes evolved due to novelty in gene regulation, such as that caused by genome rewiring. This has been demonstrated by comparing common regulatory sequences among species and by identifying single regulatory mutations that are associated with new phenotypes. However, while a single mutation changes a single element, gene regulation is accomplished by a regulatory network involving multiple interactive elements. Therefore, to better understand regulatory evolution, we have studied how mutations contributed to the adaptation of cells to a regulatory challenge. We created a synthetic genome rewiring in yeast cells, challenged their gene regulation, and studied their adaptation. HIS3, an essential enzyme for histidine biosynthesis, was placed exclusively under a GAL promoter, which is induced by galactose and strongly repressed in glucose. Such rewired cells were faced with significant regulatory challenges in a repressive glucose medium. We identified several independent mutations in elements of the GAL system associated with the rapid adaptation of cells, such as the repressor GAL80 and the binding sites of the activator GAL4. Consistent with the extraordinarily high rate of cell adaptation, new regulation emerged during adaptation via multiple trajectories, including those involving mutations in elements of the GAL system. The new regulation of HIS3 tuned its expression according to histidine requirements with or without these significant mutations, indicating that additional factors participated in this regulation and that the regulatory network could reorganize in multiple ways to accommodate different mutations. This study, therefore, stresses network plasticity as an important property for regulatory adaptation and evolution.

Synthetic Biology of Phenotypic Adaptation in Vertebrates: The Next Frontier

Synthetic Biology of Phenotypic Adaptation in Vertebrates: The Next Frontier:
For over the last 2 decades, positively selected amino acid sites have been inferred almost exclusively by showing that the number of nonsynonymous substitutions per nonsynonymous site (dn) is greater than that of synonymous substitutions per synonymous site (ds). However, virtually none of these statistical results have been experimentally tested and remain as hypotheses. To perform such experimental tests, we must connect genotype and phenotype and relate the phenotypic changes to the environmental and behavioral changes of the organism. The genotype–phenotype relationship can be established only by synthesizing and manipulating "proper" ancestral phenotypes, whereas the actual functions of adaptive mutations can be learned by studying their chemical roles in phenotypic changes.

Gene regulation: mRNA decay factors regulate transcription

Gene regulation: mRNA decay factors regulate transcription:
Nature Reviews Genetics 14, 444 (2013).
doi:10.1038/nrg3530

Author: Mary Muers
Levels of mRNAs depend on the balance of their synthesis and decay; this study reveals a way in which the two processes are intimately connected. Working in yeast, Haimovich et al. found that components of the cytoplasmic 5′ to 3′ decay pathway (collectively known

Evo–Devo: Flowering form

Evo–Devo: Flowering form:
Nature Reviews Genetics 14, 442 (2013).
doi:10.1038/nrg3516

Author: Mary Muers
The evolution of diverse organ shapes — such as intricate petals and leaves — has long fascinated biologists. A fundamental question is whether organs share an underlying developmental framework that has evolved under different selective pressures to form unique structures. This is indeed the case

Saturday, June 15, 2013

Dynamics and stoichiometry of a regulated enhancer-binding protein in live Escherichia coli cells

Dynamics and stoichiometry of a regulated enhancer-binding protein in live Escherichia coli cells:
Article
Cellular adaptive responses require temporal and spatial control of key regulatory protein complexes. Mehta et al. describe the dynamic interaction of a transcriptional activator mediating membrane stress response in E. coli with its negative regulator, the cell membrane and the transcription machinery.
Nature Communications doi: 10.1038/ncomms2997
Authors: Parul Mehta, Goran Jovanovic, Tchern Lenn, Andreas Bruckbauer, Christoph Engl, Liming Ying, Martin Buck

Wednesday, June 12, 2013

Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells

Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells:
Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells

Nature 498, 7453 (2013). doi:10.1038/nature12172

Authors: Alex K. Shalek, Rahul Satija, Xian Adiconis, Rona S. Gertner, Jellert T. Gaublomme, Raktima Raychowdhury, Schraga Schwartz, Nir Yosef, Christine Malboeuf, Diana Lu, John J. Trombetta, Dave Gennert, Andreas Gnirke, Alon Goren, Nir Hacohen, Joshua Z. Levin, Hongkun Park & Aviv Regev
Recent molecular studies have shown that, even when derived from a seemingly homogenous population, individual cells can exhibit substantial differences in gene expression, protein levels and phenotypic output, with important functional consequences. Existing studies of cellular heterogeneity, however, have typically measured only a few pre-selected RNAs or proteins simultaneously, because genomic profiling methods could not be applied to single cells until very recently. Here we use single-cell RNA sequencing to investigate heterogeneity in the response of mouse bone-marrow-derived dendritic cells (BMDCs) to lipopolysaccharide. We find extensive, and previously unobserved, bimodal variation in messenger RNA abundance and splicing patterns, which we validate by RNA-fluorescence in situ hybridization for select transcripts. In particular, hundreds of key immune genes are bimodally expressed across cells, surprisingly even for genes that are very highly expressed at the population average. Moreover, splicing patterns demonstrate previously unobserved levels of heterogeneity between cells. Some of the observed bimodality can be attributed to closely related, yet distinct, known maturity states of BMDCs; other portions reflect differences in the usage of key regulatory circuits. For example, we identify a module of 137 highly variable, yet co-regulated, antiviral response genes. Using cells from knockout mice, we show that variability in this module may be propagated through an interferon feedback circuit, involving the transcriptional regulators Stat2 and Irf7. Our study demonstrates the power and promise of single-cell genomics in uncovering functional diversity between cells and in deciphering cell states and circuits.

Tuesday, June 11, 2013

Evolution of Robustness and Cellular Stochasticity of Gene Expression

Evolution of Robustness and Cellular Stochasticity of Gene Expression:
by Steven A. Frank



Gene expression varies widely in cells with the same genotype and environment [1],[2]. Predicting the patterns of stochastic cellular fluctuations remains an unsolved challenge. I propose that the degree to which varying cellular components combine to determine robust phenotypes may predict the amount of variability. Microbes provide excellent experimental models to analyze the relations between robust phenotypes and stochastic variability.

Perceptual basis of music styles [Applied Mathematics]

Perceptual basis of music styles [Applied Mathematics]: The brain processes temporal statistics to predict future events and to categorize perceptual objects. These statistics, called expectancies, are found in music perception, and they span a variety of different features and time scales. Specifically, there is evidence that music perception involves strong expectancies regarding the distribution of a melodic...


Sequential activation of ETS proteins provides a sustained transcriptional response to EGFR signaling [RESEARCH ARTICLES]

Sequential activation of ETS proteins provides a sustained transcriptional response to EGFR signaling [RESEARCH ARTICLES]: Arkadi Shwartz, Shaul Yogev, Eyal D. Schejter, and Ben-Zion Shilo



How signal transduction, which is dynamic and fluctuating by nature, is converted into a stable trancriptional response, is an unanswered question in developmental biology. Two ETS-domain transcription factors encoded by the pointed (pnt) locus, PntP1 and PntP2, are universal downstream mediators of EGFR-based signaling in Drosophila. Full disruption of pnt function in developing eye imaginal discs reveals a photoreceptor recruitment phenotype, in which only the R8 photoreceptor cell type is specified within ommatidia. Specific disruption of either pntP1 or pntP2 resulted in the same R8-only phenotype, demonstrating that both Pnt isoforms are essential for photoreceptor recruitment. We show that the two Pnt protein forms are activated in a sequential manner within the EGFR signaling pathway: MAPK phosphorylates and activates PntP2, which in turn induces pntP1 transcription. Once expressed, PntP1 is constitutively active and sufficient to induce target genes essential for photoreceptor development. Pulse-chase experiments indicate that PntP1 is stable for several hours in the eye disc. Sequential ETS-protein recruitment therefore allows sustained induction of target genes, beyond the transient activation of EGFR.

Friday, June 7, 2013

TherMos: Estimating protein-DNA binding energies from in vivo binding profiles

TherMos: Estimating protein-DNA binding energies from in vivo binding profiles:
Accurately characterizing transcription factor (TF)-DNA affinity is a central goal of regulatory genomics. Although thermodynamics provides the most natural language for describing the continuous range of TF-DNA affinity, traditional motif discovery algorithms focus instead on classification paradigms that aim to discriminate ‘bound’ and ‘unbound’ sequences. Moreover, these algorithms do not directly model the distribution of tags in ChIP-seq data. Here, we present a new algorithm named Thermodynamic Modeling of ChIP-seq (TherMos), which directly estimates a position-specific binding energy matrix (PSEM) from ChIP-seq/exo tag profiles. In cross-validation tests on seven genome-wide TF-DNA binding profiles, one of which we generated via ChIP-seq on a complex developing tissue, TherMos predicted quantitative TF-DNA binding with greater accuracy than five well-known algorithms. We experimentally validated TherMos binding energy models for Klf4 and Esrrb, using a novel protocol to measure PSEMs in vitro. Strikingly, our measurements revealed strong non-additivity at multiple positions within the two PSEMs. Among the algorithms tested, only TherMos was able to model the entire binding energy landscape of Klf4 and Esrrb. Our study reveals new insights into the energetics of TF-DNA binding in vivo and provides an accurate first-principles approach to binding energy inference from ChIP-seq and ChIP-exo data.

Thursday, June 6, 2013

Scaling of Dorsal-Ventral Patterning by Embryo Size-Dependent Degradation of Spemann’s Organizer Signals

Scaling of Dorsal-Ventral Patterning by Embryo Size-Dependent Degradation of Spemann’s Organizer Signals: Hidehiko Inomata, Tatsuo Shibata, Tomoko Haraguchi, Yoshiki Sasai. Spemann’s organizer plays a key role in dorsal-ventral (DV) patterning in the amphibian embryo by secreting diffusible proteins such as Chordin, an antagonist to ventralizing bone morphogenetic pr....

[Special Issue Review] Imaging Morphogenesis: Technological Advances and Biological Insights

[Special Issue Review] Imaging Morphogenesis: Technological Advances and Biological Insights: Author: Philipp J. Keller

[Research Article] A Switch Between Topological Domains Underlies HoxD Genes Collinearity in Mouse Limbs

[Research Article] A Switch Between Topological Domains Underlies HoxD Genes Collinearity in Mouse Limbs: Regulation of the HoxD gene cluster switches from one side of the cluster to the other in parallel with limb development. [Also see Perspective by Rauch and Carlezon]

Authors: Guillaume Andrey, Thomas Montavon, Bénédicte Mascrez, Federico Gonzalez, Daan Noordermeer, Marion Leleu, Didier Trono, François Spitz, Denis Duboule

[Report] Stepwise Evolution of Essential Centromere Function in a Drosophila Neogene

[Report] Stepwise Evolution of Essential Centromere Function in a Drosophila Neogene: How does a recently evolved gene come to encode an essential function?

Authors: Benjamin D. Ross, Leah Rosin, Andreas W. Thomae, Mary Alice Hiatt, Danielle Vermaak, Aida Flor A. de la Cruz, Axel Imhof, Barbara G. Mellone, Harmit S. Malik

[Special Issue Review] Mechanics of Epithelial Tissue Homeostasis and Morphogenesis

[Special Issue Review] Mechanics of Epithelial Tissue Homeostasis and Morphogenesis: Authors: Charlène Guillot, Thomas Lecuit

[Perspective] Developmental Biology: Deserts and Waves in Gene Expression

[Perspective] Developmental Biology: Deserts and Waves in Gene Expression: A gene cluster that regulates limb development is controlled in two phases by regulatory elements that flank the cluster and operate independently. [Also see Research Article by Andrey et al.]

Authors: Alan R. Rodrigues, Clifford J. Tabin

A Genome-Wide, Fine-Scale Map of Natural Pigmentation Variation in Drosophila melanogaster

A Genome-Wide, Fine-Scale Map of Natural Pigmentation Variation in Drosophila melanogaster:
by Héloïse Bastide, Andrea Betancourt, Viola Nolte, Raymond Tobler, Petra Stöbe, Andreas Futschik, Christian Schlötterer



Various approaches can be applied to uncover the genetic basis of natural phenotypic variation, each with their specific strengths and limitations. Here, we use a replicated genome-wide association approach (Pool-GWAS) to fine-scale map genomic regions contributing to natural variation in female abdominal pigmentation in Drosophila melanogaster, a trait that is highly variable in natural populations and highly heritable in the laboratory. We examined abdominal pigmentation phenotypes in approximately 8000 female European D. melanogaster, isolating 1000 individuals with extreme phenotypes. We then used whole-genome Illumina sequencing to identify single nucleotide polymorphisms (SNPs) segregating in our sample, and tested these for associations with pigmentation by contrasting allele frequencies between replicate pools of light and dark individuals. We identify two small regions near the pigmentation genes tan and bric-à-brac 1, both corresponding to known cis-regulatory regions, which contain SNPs showing significant associations with pigmentation variation. While the Pool-GWAS approach suffers some limitations, its cost advantage facilitates replication and it can be applied to any non-model system with an available reference genome.

Wednesday, June 5, 2013

Architecture and evolution of a minute plant genome

Architecture and evolution of a minute plant genome:
Architecture and evolution of a minute plant genome

Nature 498, 7452 (2013). doi:10.1038/nature12132

Authors: Enrique Ibarra-Laclette, Eric Lyons, Gustavo Hernández-Guzmán, Claudia Anahí Pérez-Torres, Lorenzo Carretero-Paulet, Tien-Hao Chang, Tianying Lan, Andreanna J. Welch, María Jazmín Abraham Juárez, June Simpson, Araceli Fernández-Cortés, Mario Arteaga-Vázquez, Elsa Góngora-Castillo, Gustavo Acevedo-Hernández, Stephan C. Schuster, Heinz Himmelbauer, André E. Minoche, Sen Xu, Michael Lynch, Araceli Oropeza-Aburto, Sergio Alan Cervantes-Pérez, María de Jesús Ortega-Estrada, Jacob Israel Cervantes-Luevano, Todd P. Michael, Todd Mockler, Douglas Bryant, Alfredo Herrera-Estrella, Victor A. Albert & Luis Herrera-Estrella
It has been argued that the evolution of plant genome size is principally unidirectional and increasing owing to the varied action of whole-genome duplications (WGDs) and mobile element proliferation. However, extreme genome size reductions have been reported in the angiosperm family tree. Here we report the sequence of the 82-megabase genome of the carnivorous bladderwort plant Utricularia gibba. Despite its tiny size, the U. gibba genome accommodates a typical number of genes for a plant, with the main difference from other plant genomes arising from a drastic reduction in non-genic DNA. Unexpectedly, we identified at least three rounds of WGD in U. gibba since common ancestry with tomato (Solanum) and grape (Vitis). The compressed architecture of the U. gibba genome indicates that a small fraction of intergenic DNA, with few or no active retrotransposons, is sufficient to regulate and integrate all the processes required for the development and reproduction of a complex organism.

Posthumous reproduction in male guppies

Posthumous reproduction in male guppies:
In semelparous populations, dormant germ banks (e.g. seeds) have been proposed as important in maintaining genotypes that are adaptive at different times in fluctuating environments. Such hidden storage of genetic diversity need not be exclusive to dormant banks. Genotype diversity may be preserved in many iteroparous animals through sperm-storage mechanisms in females. This allows males to reproduce posthumously and increase the effective sizes of seemingly female-biased populations. Although long-term sperm storage has been demonstrated in many organisms, the understanding of its importance in the wild is very poor. We here show the prevalence of male posthumous reproduction in wild Trinidadian guppies, through the combination of mark–recapture and pedigree analyses of a multigenerational individual-based dataset. A significant proportion of the reproductive population consisted of dead males, who could conceive up to 10 months after death (the maximum allowed by the length of the dataset), which is more than twice the estimated generation time. Demographic analysis shows that the fecundity of dead males can play an important role in population growth and selection.

Tuesday, June 4, 2013

Regulatory disease-associated variants [Systems Biology]

Regulatory disease-associated variants [Systems Biology]: Genome-wide association studies have discovered many genetic loci associated with disease traits, but the functional molecular basis of these associations is often unresolved. Genome-wide regulatory and gene expression profiles measured across individuals and diseases reflect downstream effects of genetic variation and may allow for functional assessment of disease-associated loci. Here,...

Evolution of an ancient plant bHLH network [Plant Biology]

Evolution of an ancient plant bHLH network [Plant Biology]:



The evolution of multicellular organisms was made possible by the evolution of underlying gene regulatory networks. In animals, the core of gene regulatory networks consists of kernels, stable subnetworks of transcription factors that are highly conserved in distantly related species. However, in plants it is not clear when and how...

Sunday, June 2, 2013

Arboretum: Reconstruction and analysis of the evolutionary history of condition-specific transcriptional modules [METHOD]

Arboretum: Reconstruction and analysis of the evolutionary history of condition-specific transcriptional modules [METHOD]:
Comparative functional genomics studies the evolution of biological processes by analyzing functional data, such as gene expression profiles, across species. A major challenge is to compare profiles collected in a complex phylogeny. Here, we present Arboretum, a novel scalable computational algorithm that integrates expression data from multiple species with species and gene phylogenies to infer modules of coexpressed genes in extant species and their evolutionary histories. We also develop new, generally applicable measures of conservation and divergence in gene regulatory modules to assess the impact of changes in gene content and expression on module evolution. We used Arboretum to study the evolution of the transcriptional response to heat shock in eight species of Ascomycota fungi and to reconstruct modules of the ancestral environmental stress response (ESR). We found substantial conservation in the stress response across species and in the reconstructed components of the ancestral ESR modules. The greatest divergence was in the most induced stress, primarily through module expansion. The divergence of the heat stress response exceeds that observed in the response to glucose depletion in the same species. Arboretum and its associated analyses provide a comprehensive framework to systematically study regulatory evolution of condition-specific responses.

Integrative analysis of C. elegans modENCODE ChIP-seq data sets to infer gene regulatory interactions [RESEARCH]

Integrative analysis of C. elegans modENCODE ChIP-seq data sets to infer gene regulatory interactions [RESEARCH]:
The C. elegans modENCODE Consortium has defined in vivo binding sites for a large array of transcription factors by ChIP-seq. In this article, we present examples that illustrate how this compendium of ChIP-seq data can drive biological insights not possible with analysis of individual factors. First, we analyze the number of independent factors bound to the same locus, termed transcription factor complexity, and find that low-complexity sites are more likely to respond to altered expression of a single bound transcription factor. Next, we show that comparison of binding sites for the same factor across developmental stages can reveal insight into the regulatory network of that factor, as we find that the transcription factor UNC-62 has distinct binding profiles at different stages due to distinct cofactor co-association as well as tissue-specific alternative splicing. Finally, we describe an approach to infer potential regulators of gene expression changes found in profiling experiments (such as DNA microarrays) by screening these altered genes to identify significant enrichment for targets of a transcription factor identified in ChIP-seq data sets. After confirming that this approach can correctly identify the upstream regulator on expression data sets for which the regulator was previously known, we applied this approach to identify novel candidate regulators of transcriptional changes with age. The analysis revealed nine candidate aging regulators, of which three were previously known to have a role in longevity. We experimentally showed that two of the new candidate aging regulators can extend lifespan when overexpressed, indicating that this approach can identify novel functional regulators of complex processes.

Global analysis of Drosophila Cys2-His2 zinc finger proteins reveals a multitude of novel recognition motifs and binding determinants [RESEARCH]

Global analysis of Drosophila Cys2-His2 zinc finger proteins reveals a multitude of novel recognition motifs and binding determinants [RESEARCH]:
Cys2-His2 zinc finger proteins (ZFPs) are the largest group of transcription factors in higher metazoans. A complete characterization of these ZFPs and their associated target sequences is pivotal to fully annotate transcriptional regulatory networks in metazoan genomes. As a first step in this process, we have characterized the DNA-binding specificities of 129 zinc finger sets from Drosophila using a bacterial one-hybrid system. This data set contains the DNA-binding specificities for at least one encoded ZFP from 70 unique genes and 23 alternate splice isoforms representing the largest set of characterized ZFPs from any organism described to date. These recognition motifs can be used to predict genomic binding sites for these factors within the fruit fly genome. Subsets of fingers from these ZFPs were characterized to define their orientation and register on their recognition sequences, thereby allowing us to define the recognition diversity within this finger set. We find that the characterized fingers can specify 47 of the 64 possible DNA triplets. To confirm the utility of our finger recognition models, we employed subsets of Drosophila fingers in combination with an existing archive of artificial zinc finger modules to create ZFPs with novel DNA-binding specificity. These hybrids of natural and artificial fingers can be used to create functional zinc finger nucleases for editing vertebrate genomes.

A dynamic H3K27ac signature identifies VEGFA-stimulated endothelial enhancers and requires EP300 activity [RESEARCH]

A dynamic H3K27ac signature identifies VEGFA-stimulated endothelial enhancers and requires EP300 activity [RESEARCH]:
Histone modifications are now well-established mediators of transcriptional programs that distinguish cell states. However, the kinetics of histone modification and their role in mediating rapid, signal-responsive gene expression changes has been little studied on a genome-wide scale. Vascular endothelial growth factor A (VEGFA), a major regulator of angiogenesis, triggers changes in transcriptional activity of human umbilical vein endothelial cells (HUVECs). Here, we used chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) to measure genome-wide changes in histone H3 acetylation at lysine 27 (H3K27ac), a marker of active enhancers, in unstimulated HUVECs and HUVECs stimulated with VEGFA for 1, 4, and 12 h. We show that sites with the greatest H3K27ac change upon stimulation were associated tightly with EP300, a histone acetyltransferase. Using the variation of H3K27ac as a novel epigenetic signature, we identified transcriptional regulatory elements that are functionally linked to angiogenesis, participate in rapid VEGFA-stimulated changes in chromatin conformation, and mediate VEGFA-induced transcriptional responses. Dynamic H3K27ac deposition and associated changes in chromatin conformation required EP300 activity instead of altered nucleosome occupancy or changes in DNase I hypersensitivity. EP300 activity was also required for a subset of dynamic H3K27ac sites to loop into proximity of promoters. Our study identified thousands of endothelial, VEGFA-responsive enhancers, demonstrating that an epigenetic signature based on the variation of a chromatin feature is a productive approach to define signal-responsive genomic elements. Further, our study implicates global epigenetic modifications in rapid, signal-responsive transcriptional regulation.