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Distinct Cis Regulatory Elements Govern the Expression of TAG1 in Embryonic Sensory Ganglia and Spinal Cord  [PDF]
Yoav Hadas, Noa Nitzan, Andrew J. W. Furley, Serguei V. Kozlov, Avihu Klar
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057960
Abstract: Cell fate commitment of spinal progenitor neurons is initiated by long-range, midline-derived, morphogens that regulate an array of transcription factors that, in turn, act sequentially or in parallel to control neuronal differentiation. Included among these are transcription factors that regulate the expression of receptors for guidance cues, thereby determining axonal trajectories. The Ig/FNIII superfamily molecules TAG1/Axonin1/CNTN2 (TAG1) and Neurofascin (Nfasc) are co-expressed in numerous neuronal cell types in the CNS and PNS – for example motor, DRG and interneurons - both promote neurite outgrowth and both are required for the architecture and function of nodes of Ranvier. The genes encoding TAG1 and Nfasc are adjacent in the genome, an arrangement which is evolutionarily conserved. To study the transcriptional network that governs TAG1 and Nfasc expression in spinal motor and commissural neurons, we set out to identify cis elements that regulate their expression. Two evolutionarily conserved DNA modules, one located between the Nfasc and TAG1 genes and the second directly 5′ to the first exon and encompassing the first intron of TAG1, were identified that direct complementary expression to the CNS and PNS, respectively, of the embryonic hindbrain and spinal cord. Sequential deletions and point mutations of the CNS enhancer element revealed a 130bp element containing three conserved E-boxes required for motor neuron expression. In combination, these two elements appear to recapitulate a major part of the pattern of TAG1 expression in the embryonic nervous system.
Gene Set-Based Module Discovery Decodes cis-Regulatory Codes Governing Diverse Gene Expression across Human Multiple Tissues  [PDF]
Atsushi Niida,Seiya Imoto,Rui Yamaguchi,Masao Nagasaki,Satoru Miyano
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010910
Abstract: Decoding transcriptional programs governing transcriptomic diversity across human multiple tissues is a major challenge in bioinformatics. To address this problem, a number of computational methods have focused on cis-regulatory codes driving overexpression or underexpression in a single tissue as compared to others. On the other hand, we recently proposed a different approach to mine cis-regulatory codes: starting from gene sets sharing common cis-regulatory motifs, the method screens for expression modules based on expression coherence. However, both approaches seem to be insufficient to capture transcriptional programs that control gene expression in a subset of all samples. Especially, this limitation would be serious when analyzing multiple tissue data. To overcome this limitation, we developed a new module discovery method termed BEEM (Biclusering-based Extraction of Expression Modules) in order to discover expression modules that are functional in a subset of tissues. We showed that, when applied to expression profiles of human multiple tissues, BEEM finds expression modules missed by two existing approaches that are based on the coherent expression and the single tissue-specific differential expression. From the BEEM results, we obtained new insights into transcriptional programs controlling transcriptomic diversity across various types of tissues. This study introduces BEEM as a powerful tool for decoding regulatory programs from a compendium of gene expression profiles.
Identification of cis-Regulatory Elements in the dmyc Gene of Drosophila Melanogaster
Jasmine Kharazmi, Cameron Moshfegh and Thomas Brody
Gene Regulation and Systems Biology , 2012, DOI: 10.4137/GRSB.S8044
Abstract: Myc is a crucial regulator of growth and proliferation during animal development. Many signals and transcription factors lead to changes in the expression levels of Drosophila myc, yet no clear model exists to explain the complexity of its regulation at the level of transcription. In this study we used Drosophila genetic tools to track the dmyc cis-regulatory elements. Bioinformatics analyses identified conserved sequence blocks in the noncoding regions of the dmyc gene. Investigation of lacZ reporter activity driven by upstream, downstream, and intronic sequences of the dmyc gene in embryonic, larval imaginal discs, larval brain, and adult ovaries, revealed that it is likely to be transcribed from multiple transcription initiation units including a far upstream regulatory region, a TATA box containing proximal complex and a TATA-less downstream promoter element in conjunction with an initiator within the intron 2 region. Our data provide evidence for a modular organization of dmyc regulatory sequences; these modules will most likely be required to generate the tissue-specific patterns of dmyc transcripts. The far upstream region is active in late embryogenesis, while activity of other cis elements is evident during embryogenesis, in specific larval imaginal tissues and during oogenesis. These data provide a framework for further investigation of the transcriptional regulatory mechanisms of dmyc.
Systematic Identification of cis-Regulatory Sequences Active in Mouse and Human Embryonic Stem Cells  [PDF]
Marica Grskovic equal contributor,Christina Chaivorapol equal contributor,Alexandre Gaspar-Maia,Hao Li ,Miguel Ramalho-Santos
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030145
Abstract: Understanding the transcriptional regulation of pluripotent cells is of fundamental interest and will greatly inform efforts aimed at directing differentiation of embryonic stem (ES) cells or reprogramming somatic cells. We first analyzed the transcriptional profiles of mouse ES cells and primordial germ cells and identified genes upregulated in pluripotent cells both in vitro and in vivo. These genes are enriched for roles in transcription, chromatin remodeling, cell cycle, and DNA repair. We developed a novel computational algorithm, CompMoby, which combines analyses of sequences both aligned and non-aligned between different genomes with a probabilistic segmentation model to systematically predict short DNA motifs that regulate gene expression. CompMoby was used to identify conserved overrepresented motifs in genes upregulated in pluripotent cells. We show that the motifs are preferentially active in undifferentiated mouse ES and embryonic germ cells in a sequence-specific manner, and that they can act as enhancers in the context of an endogenous promoter. Importantly, the activity of the motifs is conserved in human ES cells. We further show that the transcription factor NF-Y specifically binds to one of the motifs, is differentially expressed during ES cell differentiation, and is required for ES cell proliferation. This study provides novel insights into the transcriptional regulatory networks of pluripotent cells. Our results suggest that this systematic approach can be broadly applied to understanding transcriptional networks in mammalian species.
Functional Evolution of cis-Regulatory Modules at a Homeotic Gene in Drosophila  [PDF]
Margaret C. W. Ho equal contributor,Holly Johnsen equal contributor,Sara E. Goetz equal contributor,Benjamin J. Schiller,Esther Bae,Diana A. Tran,Andrey S. Shur,John M. Allen,Christoph Rau,Welcome Bender,William W. Fisher,Susan E. Celniker,Robert A. Drewell
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000709
Abstract: It is a long-held belief in evolutionary biology that the rate of molecular evolution for a given DNA sequence is inversely related to the level of functional constraint. This belief holds true for the protein-coding homeotic (Hox) genes originally discovered in Drosophila melanogaster. Expression of the Hox genes in Drosophila embryos is essential for body patterning and is controlled by an extensive array of cis-regulatory modules (CRMs). How the regulatory modules functionally evolve in different species is not clear. A comparison of the CRMs for the Abdominal-B gene from different Drosophila species reveals relatively low levels of overall sequence conservation. However, embryonic enhancer CRMs from other Drosophila species direct transgenic reporter gene expression in the same spatial and temporal patterns during development as their D. melanogaster orthologs. Bioinformatic analysis reveals the presence of short conserved sequences within defined CRMs, representing gap and pair-rule transcription factor binding sites. One predicted binding site for the gap transcription factor KRUPPEL in the IAB5 CRM was found to be altered in Superabdominal (Sab) mutations. In Sab mutant flies, the third abdominal segment is transformed into a copy of the fifth abdominal segment. A model for KRUPPEL-mediated repression at this binding site is presented. These findings challenge our current understanding of the relationship between sequence evolution at the molecular level and functional activity of a CRM. While the overall sequence conservation at Drosophila CRMs is not distinctive from neighboring genomic regions, functionally critical transcription factor binding sites within embryonic enhancer CRMs are highly conserved. These results have implications for understanding mechanisms of gene expression during embryonic development, enhancer function, and the molecular evolution of eukaryotic regulatory modules.
Parallel Evolution of Chordate Cis-Regulatory Code for Development  [PDF]
Laura Doglio,Debbie K. Goode,Maria C. Pelleri,Stefan Pauls,Flavia Frabetti,Sebastian M. Shimeld,Tanya Vavouri ,Greg Elgar
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003904
Abstract: Urochordates are the closest relatives of vertebrates and at the larval stage, possess a characteristic bilateral chordate body plan. In vertebrates, the genes that orchestrate embryonic patterning are in part regulated by highly conserved non-coding elements (CNEs), yet these elements have not been identified in urochordate genomes. Consequently the evolution of the cis-regulatory code for urochordate development remains largely uncharacterised. Here, we use genome-wide comparisons between C. intestinalis and C. savignyi to identify putative urochordate cis-regulatory sequences. Ciona conserved non-coding elements (ciCNEs) are associated with largely the same key regulatory genes as vertebrate CNEs. Furthermore, some of the tested ciCNEs are able to activate reporter gene expression in both zebrafish and Ciona embryos, in a pattern that at least partially overlaps that of the gene they associate with, despite the absence of sequence identity. We also show that the ability of a ciCNE to up-regulate gene expression in vertebrate embryos can in some cases be localised to short sub-sequences, suggesting that functional cross-talk may be defined by small regions of ancestral regulatory logic, although functional sub-sequences may also be dispersed across the whole element. We conclude that the structure and organisation of cis-regulatory modules is very different between vertebrates and urochordates, reflecting their separate evolutionary histories. However, functional cross-talk still exists because the same repertoire of transcription factors has likely guided their parallel evolution, exploiting similar sets of binding sites but in different combinations.
Expression-Guided In Silico Evaluation of Candidate Cis Regulatory Codes for Drosophila Muscle Founder Cells  [PDF]
Anthony A Philippakis ,Brian W Busser ,Stephen S Gisselbrecht,Fangxue Sherry He,Beatriz Estrada,Alan M Michelson ,Martha L Bulyk
PLOS Computational Biology , 2006, DOI: 10.1371/journal.pcbi.0020053
Abstract: While combinatorial models of transcriptional regulation can be inferred for metazoan systems from a priori biological knowledge, validation requires extensive and time-consuming experimental work. Thus, there is a need for computational methods that can evaluate hypothesized cis regulatory codes before the difficult task of experimental verification is undertaken. We have developed a novel computational framework (termed “CodeFinder”) that integrates transcription factor binding site and gene expression information to evaluate whether a hypothesized transcriptional regulatory model (TRM; i.e., a set of co-regulating transcription factors) is likely to target a given set of co-expressed genes. Our basic approach is to simultaneously predict cis regulatory modules (CRMs) associated with a given gene set and quantify the enrichment for combinatorial subsets of transcription factor binding site motifs comprising the hypothesized TRM within these predicted CRMs. As a model system, we have examined a TRM experimentally demonstrated to drive the expression of two genes in a sub-population of cells in the developing Drosophila mesoderm, the somatic muscle founder cells. This TRM was previously hypothesized to be a general mode of regulation for genes expressed in this cell population. In contrast, the present analyses suggest that a modified form of this cis regulatory code applies to only a subset of founder cell genes, those whose gene expression responds to specific genetic perturbations in a similar manner to the gene on which the original model was based. We have confirmed this hypothesis by experimentally discovering six (out of 12 tested) new CRMs driving expression in the embryonic mesoderm, four of which drive expression in founder cells.
Complexity of cis-regulatory organization of six3a during forebrain and eye development in zebrafish
Chung-Hao Chao, Horng-Dar Wang, Chiou-Hwa Yuh
BMC Developmental Biology , 2010, DOI: 10.1186/1471-213x-10-35
Abstract: To elucidate the transcriptional regulation of six3a, we performed an in vivo reporter assay. Alignment of the 21-kb region surrounding the zebrafish six3a gene with the analogous region from different species identified several conserved non-coding modules. Transgenesis in zebrafish identified two enhancer elements and one suppressor. The D module drives the GFP reporter in the forebrain and eyes at an early stage, while the A module is responsible for the later expression. The A module also works as a repressor suppressing ectopic expression from the D module. Mutational analysis further minimized the A module to four highly conserved elements and the D module to three elements. Using electrophoresis mobility shift assays, we also provided evidence for the presence of DNA-binding proteins in embryonic nuclear extracts. The transcription factors that may occupy those highly conserved elements were also predicted.This study provides a comprehensive view of six3a transcription regulation during brain and eye development and offers an opportunity to establish the gene regulatory networks underlying neurogenesis in zebrafish.Zebrafish (Danio rerio) has long been an excellent vertebrate model organism for developmental biology [1-3] and is used to study the mechanisms of axis formation [4], endoderm differentiation [3,5] and muscle development [6]. It was also recently suggested to be an excellent model system for eye genetics [7]. Development is controlled by the hierarchical regulation between signaling pathways and transcription factors. The basic operating principle for specifying a territory or regulatory state is controlled coordinately by transcription factors and signal transduction machinery in the cis-regulatory code. Gene regulatory networks (GRNs) for early embryogenesis have been established in sea urchin mesendoderm [8], Xenopus endoderm [9], Drosophila dorsal/ventral polarity [10] and zebrafish mesendoderm [11]. It is essential to decode the cis-regulator
Statistical significance of cis-regulatory modules
Dustin E Schones, Andrew D Smith, Michael Q Zhang
BMC Bioinformatics , 2007, DOI: 10.1186/1471-2105-8-19
Abstract: We introduce methods designed for the detection and statistical evaluation of cis-regulatory modules, modeled as either clusters of individual binding sites or as combinations of sites with constrained organization. In order to determine the statistical significance of module sites, we first need a method to determine the statistical significance of single transcription factor binding site matches. We introduce a straightforward method of estimating the statistical significance of single site matches using a database of known promoters to produce data structures that can be used to estimate p-values for binding site matches. We next introduce a technique to calculate the statistical significance of the arrangement of binding sites within a module using a max-gap model. If the module scanned for has defined organizational parameters, the probability of the module is corrected to account for organizational constraints. The statistical significance of single site matches and the architecture of sites within the module can be combined to provide an overall estimation of statistical significance of cis-regulatory module sites.The methods introduced in this paper allow for the detection and statistical evaluation of single transcription factor binding sites and cis-regulatory modules. The features described are implemented in the Search Tool for Occurrences of Regulatory Motifs (STORM) and MODSTORM software.The identification of transcription factor binding sites and cis-regulatory modules is a crucial step in the study of gene regulation. Transcription factor binding sites often occur together in clusters as cis-regulatory modules and these modules can regulate the transcription of genes 100 kilobases (kb) or further from the module sites [1,2]. To study the regulation of transcription in silico, it has become necessary to scan large intergenic regions for occurrences of these modules. When scanning through large intergenic regions, it is important to be able to evaluate
Functional Evolution of a cis-Regulatory Module  [PDF]
Michael Z. Ludwig,Arnar Palsson,Elena Alekseeva,Casey M. Bergman,Janaki Nathan,Martin Kreitman
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0030093
Abstract: Lack of knowledge about how regulatory regions evolve in relation to their structure–function may limit the utility of comparative sequence analysis in deciphering cis-regulatory sequences. To address this we applied reverse genetics to carry out a functional genetic complementation analysis of a eukaryotic cis-regulatory module—the even-skipped stripe 2 enhancer—from four Drosophila species. The evolution of this enhancer is non-clock-like, with important functional differences between closely related species and functional convergence between distantly related species. Functional divergence is attributable to differences in activation levels rather than spatiotemporal control of gene expression. Our findings have implications for understanding enhancer structure–function, mechanisms of speciation and computational identification of regulatory modules.
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