scholarly journals Predicting effective microRNA target sites in mammalian mRNAs

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Vikram Agarwal ◽  
George W Bell ◽  
Jin-Wu Nam ◽  
David P Bartel
Keyword(s):  
Regulatory Networks ◽  
Quantitative Model ◽  
Seed Region ◽  
Microrna Target ◽  
Functional Sites ◽  
Uv Crosslinking ◽  
Gene Regulatory ◽  
Mirna Seed ◽  
Better Than

MicroRNA targets are often recognized through pairing between the miRNA seed region and complementary sites within target mRNAs, but not all of these canonical sites are equally effective, and both computational and in vivo UV-crosslinking approaches suggest that many mRNAs are targeted through non-canonical interactions. Here, we show that recently reported non-canonical sites do not mediate repression despite binding the miRNA, which indicates that the vast majority of functional sites are canonical. Accordingly, we developed an improved quantitative model of canonical targeting, using a compendium of experimental datasets that we pre-processed to minimize confounding biases. This model, which considers site type and another 14 features to predict the most effectively targeted mRNAs, performed significantly better than existing models and was as informative as the best high-throughput in vivo crosslinking approaches. It drives the latest version of TargetScan (v7.0; targetscan.org), thereby providing a valuable resource for placing miRNAs into gene-regulatory networks.

scholarly journals Predicting microRNA targeting efficacy in Drosophila

2017 ◽  
Author(s):  
Vikram Agarwal ◽  
Alexander O. Subtelny ◽  
Prathapan Thiru ◽  
Igor Ulitsky ◽  
David P. Bartel
Keyword(s):  
Quantitative Study ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Quantitative Model ◽  
Valuable Resource ◽  
Mrna Targets ◽  
Experimental Organism ◽  
Gene Regulatory ◽  
Better Than

ABSTRACTImportant for understanding the regulatory roles of miRNAs is the ability to predict the mRNA targets most responsive to each miRNA. Here, we acquired datasets needed for the quantitative study of microRNA targeting in Drosophila. Analyses of these data expanded the types of sites known to be effective in flies, expanded the mRNA regions with detectable targeting to include 5′ UTRs, and identified features of site context that correlate with targeting efficacy. Updated evolutionary analyses evaluated the probability of conserved targeting for each predicted site and indicated that more than a third of the Drosophila genes are preferentially conserved targets of miRNAs. Based on these results, a quantitative model was developed to predict targeting efficacy in insects. This model performed better than existing models and will drive the next version of TargetScanFly (v7.0; targetscan.org), thereby providing a valuable resource for placing miRNAs into gene-regulatory networks of this important experimental organism.

scholarly journals An Open-Source Cloud-FPGA Gene Regulatory Accelerator

2021 ◽  
Author(s):  
Lucas Bragança ◽  
Jeronimo Penha ◽  
Michael Canesche ◽  
Dener Ribeiro ◽  
José Augusto M. Nacif ◽  
...  
Keyword(s):  
Open Source ◽  
Gene Regulatory Networks ◽  
High Performance ◽  
Regulatory Networks ◽  
Cloud Services ◽  
On Demand ◽  
Speed Up ◽  
Gene Regulatory ◽  
High Level ◽  
Better Than

FPGAs are suitable to speed up gene regulatory network (GRN) algorithms with high throughput and energy efficiency. In addition, virtualizing FPGA using hardware generators and cloud resources increases the computing ability to achieve on-demand accelerations across multiple users. Recently, Amazon AWS provides high-performance Cloud's FPGAs. This work proposes an open source accelerator generator for Boolean gene regulatory networks. The generator automatically creates all hardware and software pieces from a high-level GRN description. We evaluate the accelerator performance and cost for CPU, GPU, and Cloud FPGA implementations by considering six GRN models proposed in the literature. As a result, the FPGA accelerator is at least 12x faster than the best GPU accelerator. Furthermore, the FPGA reaches the best performance per dollar in cloud services, at least 5x better than the best GPU accelerator.

scholarly journals In vitro gene regulatory networks predict in vivo function of liver

2010 ◽  
Vol 4 (1) ◽  
Author(s):  
Youping Deng ◽  
David R Johnson ◽  
Xin Guan ◽  
Choo Y Ang ◽  
Junmei Ai ◽  
...  
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Gene Regulatory

scholarly journals Identifying genetic modulators of the connectivity between transcription factors and their transcriptional targets

2016 ◽  
Vol 113 (13) ◽  
pp. E1835-E1843 ◽  
Author(s):  
Mina Fazlollahi ◽  
Ivor Muroff ◽  
Eunjee Lee ◽  
Helen C. Causton ◽  
Harmen J. Bussemaker
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Nonsynonymous Mutation ◽  
Gene Regulatory ◽  
Genetic Modulators

Regulation of gene expression by transcription factors (TFs) is highly dependent on genetic background and interactions with cofactors. Identifying specific context factors is a major challenge that requires new approaches. Here we show that exploiting natural variation is a potent strategy for probing functional interactions within gene regulatory networks. We developed an algorithm to identify genetic polymorphisms that modulate the regulatory connectivity between specific transcription factors and their target genes in vivo. As a proof of principle, we mapped connectivity quantitative trait loci (cQTLs) using parallel genotype and gene expression data for segregants from a cross between two strains of the yeast Saccharomyces cerevisiae. We identified a nonsynonymous mutation in the DIG2 gene as a cQTL for the transcription factor Ste12p and confirmed this prediction empirically. We also identified three polymorphisms in TAF13 as putative modulators of regulation by Gcn4p. Our method has potential for revealing how genetic differences among individuals influence gene regulatory networks in any organism for which gene expression and genotype data are available along with information on binding preferences for transcription factors.

scholarly journals Vegfaexpression is activated through positive and negative transcriptional regulatory networks controlled by the ETS factor Etv6in vivo

2018 ◽  
Author(s):  
Lei Li ◽  
Rossella Rispoli ◽  
Roger Patient ◽  
Aldo Ciau-Uitz ◽  
Catherine Porcher
Keyword(s):  
Regulatory Networks ◽  
Dual Function ◽  
Transcriptional Regulatory Networks ◽  
Pathological Angiogenesis ◽  
Transcriptional Regulatory ◽  
Gene Regulatory ◽  
Ets Transcription Factor ◽  
Endothelial Development ◽  
New Strategies

AbstractVEGFA signaling is crucial for physiological and pathological angiogenesis and hematopoiesis. Although many context-dependent signaling pathways downstream of VEGFA have been uncovered, vegfa transcriptional regulation in vivo remains unclear. Here we show that the ETS transcription factor, Etv6, positively regulates vegfa expression during Xenopus blood stem cell development through multiple transcriptional inputs. In agreement with its established repressive functions, Etv6 directly inhibits the expression of the vegfa repressor, foxo3. Surprisingly, it also directly activates the expression of the vegfa activator, klf4. Finally, it indirectly binds to the vegfa promoter where it co-localizes with Klf4. Klf4 deficiency downregulates vegfa expression and significantly decreases Etv6 binding to the vegfa promoter, indicating that Klf4 recruits Etv6 to the vegfa promoter. Thus, our work uncovers a dual function for Etv6, as both a transcriptional repressor and activator, in controlling a major signaling pathway involved in blood and endothelial development in vivo. Given the established relationships between development and cancer, this elaborate gene regulatory network may inform new strategies for the treatment of VEGFA-dependent tumorigenesis.

scholarly journals The emerging landscape of in vitro and in vivo epigenetic allelic effects

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2108 ◽  
Author(s):  
Christopher Gregg
Keyword(s):  
Cell Fate ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Disease Susceptibility ◽  
Monoallelic Expression ◽  
Functional Studies ◽  
Cell Type Specific ◽  
Gene Regulatory

Epigenetic mechanisms that cause maternally and paternally inherited alleles to be expressed differently in offspring have the potential to radically change our understanding of the mechanisms that shape disease susceptibility, phenotypic variation, cell fate, and gene expression. However, the nature and prevalence of these effects in vivo have been unclear and are debated. Here, I consider major new studies of epigenetic allelic effects in cell lines and primary cells and in vivo. The emerging picture is that these effects take on diverse forms, and this review attempts to clarify the nature of the different forms that have been uncovered for genomic imprinting and random monoallelic expression (RME). I also discuss apparent discrepancies between in vitro and in vivo studies. Importantly, multiple studies suggest that allelic effects are prevalent and can be developmental stage- and cell type-specific. I propose some possible functions and consider roles for allelic effects within the broader context of gene regulatory networks, cellular diversity, and plasticity. Overall, the field is ripe for discovery and is in need of mechanistic and functional studies.

scholarly journals Reconstruction of the global neural crest gene regulatory networkin vivo

2018 ◽  
Author(s):  
Ruth M Williams ◽  
Ivan Candido-Ferreira ◽  
Emmanouela Repapi ◽  
Daria Gavriouchkina ◽  
Upeka Senanayake ◽  
...  
Keyword(s):  
Neural Crest ◽  
Regulatory Networks ◽  
Transcriptome Profiling ◽  
Integrated Approach ◽  
Precise Control ◽  
Regulatory Circuits ◽  
A Genome ◽  
Gene Regulatory ◽  
Cell Transcriptome

AbstractPrecise control of developmental processes is encoded in the genome in the form of gene regulatory networks (GRNs). Such multi-factorial systems are difficult to decode in vertebrates owing to their complex gene hierarchies and transient dynamic molecular interactions. Here we present a genome-widein vivoreconstruction of the GRN underlying development of neural crest (NC), an emblematic embryonic multipotent cell population. By coupling NC-specific epigenomic and single-cell transcriptome profiling with genome/epigenome engineeringin vivo, we identify multiple regulatory layers governing NC ontogeny, including NC-specific enhancers and super-enhancers, noveltrans-factors andcis-signatures. Assembling the NC regulome has allowed the comprehensive reverse engineering of the NC-GRN at unprecedented resolution. Furthermore, identification and dissection of divergent upstream combinatorial regulatory codes has afforded new insights into opposing gene circuits that define canonical and neural NC fates. Our integrated approach, allowing dissection of cell-type-specific regulatory circuitsin vivo, has broad implications for GRN discovery and investigation.

scholarly journals Synthetic 5’ UTRs can either up- or down-regulate expression upon RBP binding

2017 ◽  
Author(s):  
Noa Katz ◽  
Roni Cohen ◽  
Oz Solomon ◽  
Beate Kaufmann ◽  
Orna Atar ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Cooperative Behavior ◽  
Transcriptional Level ◽  
Rna Molecules ◽  
Regulatory Modules ◽  
Regulatory Circuits ◽  
Rna Hairpins ◽  
Gene Regulatory ◽  
Gene Regulatory Circuits

SUMMARYThe construction of complex gene regulatory networks requires both inhibitory and up-regulatory modules. However, the vast majority of RNA-based regulatory “parts” are inhibitory. Using a synthetic biology approach combined with SHAPE-Seq, we explored the regulatory effect of RBP-RNA interactions in bacterial 5’-UTRs. By positioning a library of RNA hairpins upstream of a reporter gene and co-expressing them with the matching RBP, we observed a set of regulatory responses, including translational stimulation, translational repression, and cooperative behavior. Our combined approach revealed three distinct states in-vivo: in the absence of RBPs, the RNA molecules can be found either in a molten state that is amenable to translation, or a structured phase that inhibits translation. In the presence of RBPs, the RNA molecules are in a semi-structured phase with partial translational capacity. Our work provides new insight into RBP-based regulation and a blueprint for designing complete gene regulatory circuits at the post-transcriptional level.

scholarly journals Nuclear Transfer Arrest Embryos Show Massive Dysregulation of Genes Involved in Transcription Pathways

2021 ◽  
Vol 22 (15) ◽  
pp. 8187
Author(s):  
Chunshen Long ◽  
Hanshuang Li ◽  
Xinru Li ◽  
Wuritu Yang ◽  
Yongchun Zuo
Keyword(s):  
Gene Regulatory Networks ◽  
Nuclear Transfer ◽  
Regulatory Networks ◽  
Target Genes ◽  
Epigenetic Modification ◽  
Cell Nuclei ◽  
Activation Of Transcription ◽  
Gene Regulatory ◽  
Catabolic Process

Somatic cell nuclear transfer (SCNT) technology can reprogram terminally differentiated cell nuclei into a totipotent state. However, the underlying molecular barriers of SCNT embryo development remain incompletely elucidated. Here, we observed that transcription-related pathways were incompletely activated in nuclear transfer arrest (NTA) embryos compared to normal SCNT embryos and in vivo fertilized (WT) embryos, which hinders the development of SCNT embryos. We further revealed the transcription pathway associated gene regulatory networks (GRNs) and found the aberrant transcription pathways can lead to the massive dysregulation of genes in NTA embryos. The predicted target genes of transcription pathways contain a series of crucial factors in WT embryos, which play an important role in catabolic process, pluripotency regulation, epigenetic modification and signal transduction. In NTA embryos, however, these genes were varying degrees of inhibition and show a defect in synergy. Overall, our research found that the incomplete activation of transcription pathways is another potential molecular barrier for SCNT embryos besides the incomplete reprogramming of epigenetic modifications, broadening the understanding of molecular mechanism of SCNT embryonic development.

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