scholarly journals Enhancer–gene maps in the human and zebrafish genomes using evolutionary linkage conservation

2020 ◽  
Vol 48 (5) ◽  
pp. 2357-2371 ◽  
Author(s):  
Yves Clément ◽  
Patrick Torbey ◽  
Pascale Gilardi-Hebenstreit ◽  
Hugues Roest Crollius
Keyword(s):  
Target Genes ◽  
Genetic Diseases ◽  
Whole Genome Sequence ◽  
Regulate Gene Expression ◽  
Spatiotemporal Expression ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Gene Associations ◽  
Enhancer Sequences ◽  
Gene Maps

Abstract The spatiotemporal expression of genes is controlled by enhancer sequences that bind transcription factors. Identifying the target genes of enhancers remains difficult because enhancers regulate gene expression over long genomic distances. To address this, we used an evolutionary approach to build two genome-wide maps of predicted enhancer–gene associations in the human and zebrafish genomes. Evolutionary conserved sequences were linked to their predicted target genes using PEGASUS, a bioinformatics method that relies on evolutionary conservation of synteny. The analysis of these maps revealed that the number of predicted enhancers linked to a gene correlate with its expression breadth. Comparison of both maps identified hundreds of putative vertebrate ancestral regulatory relationships from which we could determine that predicted enhancer–gene distances scale with genome size despite strong positional conservation. The two maps represent a resource for further studies, including the prioritization of sequence variants in whole genome sequence of patients affected by genetic diseases.

scholarly journals Enhancer-gene maps in the human and zebrafish genomes using evolutionary linkage conservation

2018 ◽  
Author(s):  
Yves Clément ◽  
Patrick Torbey ◽  
Pascale Gilardi-Hebenstreit ◽  
Hugues Roest Crollius
Keyword(s):  
Target Genes ◽  
Genetic Diseases ◽  
Whole Genome Sequence ◽  
Regulate Gene Expression ◽  
Spatiotemporal Expression ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Gene Associations ◽  
Enhancer Sequences ◽  
Gene Maps

AbstractThe spatiotemporal expression of genes is controlled by enhancer sequences that bind transcription factors. Identifying the target genes of enhancers remains difficult because enhancers regulate gene expression over long genomic distances. To address this, we used an evolutionary approach to build two genome-wide maps of enhancer-gene associations in the human and zebrafish genomes. Enhancers were identified using sequence conservation, and linked to their predicted target genes using PEGASUS, a bioinformatics method that relies on evolutionary conservation of synteny. The analysis of these maps revealed that the number of enhancers linked to a gene correlate with its expression breadth. Comparison of both maps identified hundreds of vertebrate ancestral regulatory relationships from which we could determine that enhancer-gene distances scale with genome size despite strong positional conservation. The two maps represent a resource for further studies, including the prioritisation of sequence variants in whole genome sequence of patients affected by genetic diseases.

scholarly journals MicroRNAs in Uteroplacental Vascular Dysfunction

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1344 ◽  
Author(s):  
Hu ◽  
Zhang
Keyword(s):  
Intrauterine Growth Restriction ◽  
Target Genes ◽  
Vascular Dysfunction ◽  
Neonatal Morbidity ◽  
Trophoblast Invasion ◽  
Transcriptional Level ◽  
Regulate Gene Expression ◽  
Rna Molecules ◽  
Expression Of Genes ◽  
Differentially Expressed Mirnas

Pregnancy complications of preeclampsia and intrauterine growth restriction (IUGR) are major causes of maternal and perinatal/neonatal morbidity and mortality. Although their etiologies remain elusive, it is generally accepted that they are secondary to placental insufficiency conferred by both failure in spiral artery remodeling and uteroplacental vascular malfunction. MicroRNAs (miRNAs) are small no-coding RNA molecules that regulate gene expression at the post-transcriptional level. Increasing evidence suggests that miRNAs participate in virtually all biological processes and are involved in numerous human diseases. Differentially expressed miRNAs in the placenta are typical features of both preeclampsia and IUGR. Dysregulated miRNAs target genes of various signaling pathways in uteroplacental tissues, contributing to the development of both complications. In this review, we provide an overview of how aberrant miRNA expression in preeclampsia and IUGR impacts the expression of genes involved in trophoblast invasion and uteroplacental vascular adaptation.

scholarly journals Imputed gene associations identify replicable trans-acting genes enriched in transcription pathways and complex traits

2018 ◽  
Author(s):  
Heather E. Wheeler ◽  
Sally Ploch ◽  
Alvaro N. Barbeira ◽  
Rodrigo Bonazzola ◽  
Angela Andaleon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Complex Traits ◽  
Target Gene ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Nucleic Acid Binding ◽  
Expression Of Genes ◽  
Gene Associations ◽  
Made In

AbstractRegulation of gene expression is an important mechanism through which genetic variation can affect complex traits. A substantial portion of gene expression variation can be explained by both local (cis) and distal (trans) genetic variation. Much progress has been made in uncovering cis-acting expression quantitative trait loci (cis-eQTL), but trans-eQTL have been more difficult to identify and replicate. Here we take advantage of our ability to predict the cis component of gene expression coupled with gene mapping methods such as PrediXcan to identify high confidence candidate trans-acting genes and their targets. That is, we correlate the cis component of gene expression with observed expression of genes in different chromosomes. Leveraging the shared cis-acting regulation across tissues, we combine the evidence of association across all available GTEx tissues and find 2356 trans-acting/target gene pairs with high mappability scores. Reassuringly, trans-acting genes are enriched in transcription and nucleic acid binding pathways and target genes are enriched in known transcription factor binding sites. Interestingly, trans-acting genes are more significantly associated with selected complex traits and diseases than target or background genes, consistent with percolating trans effects. Our scripts and summary statistics are publicly available for future studies of trans-acting gene regulation.

scholarly journals The Wg and Dpp morphogens regulate gene expression by modulating the frequency of transcriptional bursts

2020 ◽  
Author(s):  
Rachael Bakker ◽  
Madhav Mani ◽  
Richard W. Carthew
Keyword(s):  
Regulatory Mechanisms ◽  
Burst Frequency ◽  
Regulate Gene Expression ◽  
Morphogen Gradients ◽  
Quantitative Studies ◽  
Spatiotemporal Expression ◽  
Mature Mrna ◽  
Expression Of Genes ◽  
Gene Regulatory ◽  
Transcriptional Bursting

ABSTRACTMorphogen signaling contributes to the proper spatiotemporal expression of genes during development. One method of regulation of signaling-responsive genes is at the level of transcription. Single-cell quantitative studies of transcription have revealed that transcription occurs intermittently, in bursts. Although the effects of many gene regulatory mechanisms on transcriptional bursting have been studied, it remains unclear how morphogen gradients affect this dynamic property of downstream genes. Here we have adapted smFISH for use in the Drosophila wing imaginal disc in order to measure nascent and mature mRNA of genes downstream of the Wg and Dpp morphogen gradients. We compared our experimental results with predictions from stochastic models of transcription. Our results indicate that the transcription levels of these genes appear to share a common method of control via burst frequency modulation. Our data helps further elucidate the link between developmental gene regulatory mechanisms and transcriptional bursting.

scholarly journals Identification of Key Tissue-Specific, Biological Processes by Integrating Enhancer Information in Maize Gene Regulatory Networks

2021 ◽  
Vol 11 ◽  
Author(s):  
Maud Fagny ◽  
Marieke Lydia Kuijjer ◽  
Maike Stam ◽  
Johann Joets ◽  
Olivier Turc ◽  
...  
Keyword(s):  
Regulatory Network ◽  
Regulatory Networks ◽  
Target Genes ◽  
Cell Wall Modification ◽  
Regulatory Modules ◽  
Genome Wide ◽  
A Genome ◽  
Spatio Temporal ◽  
Enhancer Sequences

Enhancers are key players in the spatio-temporal coordination of gene expression during numerous crucial processes, including tissue differentiation across development. Characterizing the transcription factors (TFs) and genes they connect, and the molecular functions underpinned is important to better characterize developmental processes. In plants, the recent molecular characterization of enhancers revealed their capacity to activate the expression of several target genes. Nevertheless, identifying these target genes at a genome-wide level is challenging, particularly for large-genome species, where enhancers and target genes can be hundreds of kilobases away. Therefore, the contribution of enhancers to plant regulatory networks remains poorly understood. Here, we investigate the enhancer-driven regulatory network of two maize tissues at different stages: leaves at seedling stage (V2-IST) and husks (bracts) at flowering. Using systems biology, we integrate genomic, epigenomic, and transcriptomic data to model the regulatory relationships between TFs and their potential target genes, and identify regulatory modules specific to husk and V2-IST. We show that leaves at the V2-IST stage are characterized by the response to hormones and macromolecules biogenesis and assembly, which are regulated by the BBR/BPC and AP2/ERF TF families, respectively. In contrast, husks are characterized by cell wall modification and response to abiotic stresses, which are, respectively, orchestrated by the C2C2/DOF and AP2/EREB families. Analysis of the corresponding enhancer sequences reveals that two different transposable element families (TIR transposon Mutator and MITE Pif/Harbinger) have shaped part of the regulatory network in each tissue, and that MITEs have provided potential new TF binding sites involved in husk tissue-specificity.

scholarly journals Hnf4a Is Required for the Development of Cdh6-Expressing Progenitors into Proximal Tubules in the Mouse Kidney

2020 ◽  
Vol 31 (11) ◽  
pp. 2543-2558 ◽  
Author(s):  
Sierra S. Marable ◽  
Eunah Chung ◽  
Joo-Seop Park
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Major Function ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Developing Kidney ◽  
Differential Gene ◽  
Direct Target ◽  
Novel Model

BackgroundHepatocyte NF 4α (Hnf4a) is a major regulator of renal proximal tubule (PT) development. In humans, a mutation in HNF4A impairs PT functions and is associated with Fanconi renotubular syndrome (FRTS). In mice, mosaic deletion of Hnf4a in the developing kidney reduces the population of PT cells, leading to FRTS-like symptoms. The molecular mechanisms underlying the role of Hnf4a in PT development remain unclear.MethodsThe gene deletion tool Osr2Cre removed Hnf4a in developing nephrons in mice, generating a novel model for FRTS. Immunofluorescence analysis characterized the mutant phenotype, and lineage analysis tested whether Cadherin-6 (Cdh6)–expressing cells are PT progenitors. Genome-wide mapping of Hnf4a binding sites and differential gene analysis of Hnf4a mutant kidneys identified direct target genes of Hnf4a.ResultsDeletion of Hnf4a with Osr2Cre led to the complete loss of mature PT cells, lethal to the Hnf4a mutant mice. Cdh6high, lotus tetragonolobus lectin-low (LTLlow) cells serve as PT progenitors and demonstrate higher proliferation than Cdh6low, LTLhigh differentiated PT cells. Additionally, Hnf4a is required for PT progenitors to differentiate into mature PT cells. Genomic analyses revealed that Hnf4a directly regulates the expression of genes involved in transmembrane transport and metabolism.ConclusionsHnf4a promotes the differentiation of PT progenitors into mature PT cells by regulating the expression of genes associated with reabsorption, the major function of PT cells.

scholarly journals SET1B facilitates activation of the hypoxia response through site-specific histone methylation

2020 ◽  
Author(s):  
Brian Ortmann ◽  
Natalie Burrows ◽  
Peter Bailey ◽  
Ian Lobb ◽  
Ana Peñalver ◽  
...  
Keyword(s):  
Histone Methylation ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Human Cancer ◽  
Selective Reduction ◽  
Low Oxygen ◽  
Site Specific ◽  
Human Cancer Cells ◽  
Expression Of Genes ◽  
Genome Wide

Abstract Hypoxia-inducible transcription factors (HIFs) are fundamental to the cellular adaptation to low oxygen levels but how they interact with chromatin and efficiently activate their target genes is unclear. Using genome-wide mutagenesis in human cancer cells, we define genes required for HIF transcriptional activation, and identify a requirement for the Histone 3 lysine 4 (H3K4) methyltransferase SET1B. Loss of SET1B leads to a selective reduction in HIF transcriptional activity in hypoxia, with SET1B driving expression of genes involved in angiogenesis rather than glycolysis, resulting in impaired tumour establishment in SET1B deficient xenografts. Mechanistically, we show that SET1B is itself oxygen regulated, accumulates on chromatin in hypoxia, and is recruited to HIF target genes through HIF-1α. Accordingly, we show that the hypoxic induction of H3K4me3 at specific HIF targets is both HIF and SET1B dependent, and when impaired, decreases promoter acetylation and gene expression. Together, these findings reveal SET1B as a determinant of site-specific histone methylation and provide insight into how HIF target genes are differentially regulated.

scholarly journals Modeling Enhancer-Promoter Interactions with Attention-Based Neural Networks

2017 ◽  
Author(s):  
Weiguang Mao ◽  
Dennis Kostka ◽  
Maria Chikina
Keyword(s):  
Dna Sequences ◽  
Target Genes ◽  
Expression Patterns ◽  
Regulatory Sequences ◽  
Learning Approaches ◽  
Interaction Prediction ◽  
Genome Wide ◽  
Gene Regulatory ◽  
Enhancer Function ◽  
Enhancer Sequences

AbstractBackgroundGene regulatory sequences play critical roles in ensuring tightly controlled RNA expression patterns that are essential in a large variety of biological processes. Specifically, enhancer sequences drive expression of their target genes, and the availability of genome-wide maps of enhancer-promoter interactions has opened up the possibility to use machine learning approaches to extract and interpret features that define these interactions in different biological contexts.MethodsInspired by machine translation models we develop an attention-based neural network model, EPIANN, to predict enhancer-promoter interactions based on DNA sequences. Codes and data are available at https://github.com/wgmao/EPIANN.ResultsOur approach accurately predicts enhancer-promoter interactions across six cell lines. In addition, our method generates pairwise attention scores at the sequence level, which specify how short regions in the enhancer and promoter pair-up to drive the interaction prediction. This allows us to identify over-represented transcription factors (TF) binding sites and TF-pair interactions in the context of enhancer function.

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