scholarly journals Splicing of enhancer-associated lincRNAs contributes to enhancer activity

2020 ◽  
Vol 3 (4) ◽  
pp. e202000663 ◽  
Author(s):  
Jennifer Y Tan ◽  
Adriano Biasini ◽  
Robert S Young ◽  
Ana C Marques
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Gene Expression Regulation ◽  
Embryonic Stem ◽  
Chromosomal Dna ◽  
Neighboring Gene ◽  
Enhancer Activity ◽  
Efficient Processing ◽  
Enhancer Function

Transcription is common at active mammalian enhancers sometimes giving rise to stable enhancer-associated long intergenic noncoding RNAs (elincRNAs). Expression of elincRNA is associated with changes in neighboring gene product abundance and local chromosomal topology, suggesting that transcription at these loci contributes to gene expression regulation in cis. Despite the lack of evidence supporting sequence-dependent functions for most elincRNAs, splicing of these transcripts is unexpectedly common. Whether elincRNA splicing is a mere consequence of cognate enhancer activity or if it directly impacts enhancer function remains unresolved. Here, we investigate the association between elincRNA splicing and enhancer activity in mouse embryonic stem cells. We show that multi-exonic elincRNAs are enriched at conserved enhancers, and the efficient processing of elincRNAs is strongly associated with their cognate enhancer activity. This association is supported by their enrichment in enhancer-specific chromatin signatures; elevated binding of co-transcriptional regulators; increased local intra-chromosomal DNA contacts; and strengthened cis-regulation on target gene expression. Our results support the role of efficient RNA processing of enhancer-associated transcripts to cognate enhancer activity.

scholarly journals An unexpected contribution of lincRNA splicing to enhancer function

2018 ◽  
Author(s):  
Jennifer Y. Tan ◽  
Adriano Biasini ◽  
Robert S. Young ◽  
Ana C. Marques
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Gene Expression Regulation ◽  
Transcriptional Regulators ◽  
Regulatory Function ◽  
Nucleotide Polymorphisms ◽  
Chromosomal Dna ◽  
Neighboring Gene ◽  
Enhancer Activity ◽  
Enhancer Function

ABSTRACTTranscription is common at active mammalian enhancers sometimes giving rise to stable and unidirectionally transcribed enhancer-associated long intergenic noncoding RNAs (elincRNAs). ElincRNA expression is associated with changes in neighboring gene product abundance and local chromosomal topology, suggesting that transcription at these loci contributes to gene expression regulation in cis. Despite the lack of evidence supporting sequence-dependent functions for most elincRNAs, splicing of these transcripts is unexpectedly common. Whether elincRNA splicing is a mere consequence of their cognate enhancer activity or if it directly impacts enhancer-associated cis-regulation remains unanswered.Here we show that elincRNAs are efficiently and rapidly spliced and that their processing rate is strongly associated with their cognate enhancer activity. This association is supported by: their enrichment in enhancer-specific chromatin signatures; elevated binding of co-transcriptional regulators, including CBP and p300; increased local intra-chromosomal DNA contacts; and strengthened cis-regulation on target gene expression. Using nucleotide polymorphisms at elincRNA splice sites, we found that elincRNA splicing enhances their transcription and directly impacts cis-regulatory function of their cognate enhancers. Importantly, up to 90% of human elincRNAs have nucleotide variants that are associated with both their splicing and the expression levels of their proximal genes.Our results highlight an unexpected contribution of elincRNA splicing to enhancer function.

scholarly journals Predictive modeling of long non-coding RNA chromatin (dis-)association

2020 ◽  
Author(s):  
Evgenia Ntini ◽  
Stefan Budach ◽  
Ulf A Vang Ørom ◽  
Annalisa Marsico
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Rna Binding ◽  
Gene Expression Regulation ◽  
Rna Binding Proteins ◽  
List Type ◽  
Enhancer Activity ◽  
Target Gene Expression ◽  
Nascent Rna ◽  
Chromatin Fractionation

SummaryLong non-coding RNAs (lncRNAs) are involved in gene expression regulation incisandtrans. Although enriched in the chromatin cell fraction, to what degree this defines their broad range of functions remains unclear. In addition, the factors that contribute to lncRNA chromatin tethering, as well as the molecular basis of efficient lncRNA chromatin dissociation and its functional impact on enhancer activity and target gene expression, remain to be resolved. Here, we combine pulse-chase metabolic labeling of nascent RNA with chromatin fractionation and transient transcriptome sequencing to follow nascent RNA transcripts from their co-transcriptional state to their release into the nucleoplasm. By incorporating functional and physical characteristics in machine learning models, we find that parameters like co-transcriptional splicing contributes to efficient lncRNA chromatin dissociation. Intriguingly, lncRNAs transcribed from enhancer-like regions display reduced chromatin retention, suggesting that, in addition to splicing, lncRNA chromatin dissociation may contribute to enhancer activity and target gene expression.HighlightsChromatin (dis-)association of lncRNAs can be modeled using nascent RNA sequencing from pulse-chase chromatin fractionationDistinct physical and functional characteristics contribute to lncRNA chromatin (dis-)associationlncRNAs transcribed from enhancers display increased degree of chromatin dissociationlncRNAs of distinct degrees of chromatin association display differential binding probabilities for RNA-binding proteins (RBPs)

Gerea: Prediction Of Gene Expression Regulators From Transcriptome Profiling Data To Transition Networks

2021 ◽  
Vol 16 ◽  
Author(s):  
Min Yao ◽  
Caiyun Jiang ◽  
Chenglong Li ◽  
Yongxia Li ◽  
Shan Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Networks ◽  
Target Gene ◽  
Gene Expression Regulation ◽  
Transcriptome Profiling ◽  
Expression Regulation ◽  
Mouse Gene ◽  
Mouse Gene Expression ◽  
Causality Inference ◽  
Identify Gene Expression

Background: Mammalian genes are regulated at the transcriptional and post-transcriptional levels. These mechanisms may involve the direct promotion or inhibition of transcription via a regulator or post-transcriptional regulation through factors such as micro (mi)RNAs. Objective: This study aimed to construct gene regulation relationships modulated by causality inference-based miRNA-(transition factor)-(target gene) networks and analyze gene expression data to identify gene expression regulators. Methods: Mouse gene expression regulation relationships were manually curated from literature using a text mining method which was then employed to generate miRNA-(transition factor)-(target gene) networks. An algorithm was then introduced to identify gene expression regulators from transcriptome profiling data by applying enrichment analysis to these networks. Results: A total of 22,271 mouse gene expression regulation relationships were curated for 4,018 genes and 242 miRNAs. GEREA software was developed to perform the integrated analyses. We applied the algorithm to transcriptome data for synthetic miR-155 oligo-treated mouse CD4+ T-cells and confirmed that miR-155 is an important network regulator. The software was also tested on publicly available transcriptional profiling data for Salmonella infection, resulting in the identification of miR-125b as an important regulator. Conclusion: The causality inference-based miRNA-(transition factor)-(target gene) networks serve as a novel resource for gene expression regulation research, and GEREA is an effective and useful adjunct to the currently available methods. The regulatory networks and the algorithm implemented in the GEREA software package are available under a free academic license at website : http://www.thua45.cn/gerea.

scholarly journals Graded Smad2/3 Activation Is Converted Directly into Levels of Target Gene Expression in Embryonic Stem Cells

PLoS ONE ◽  
2009 ◽  
Vol 4 (1) ◽  
pp. e4268 ◽  
Author(s):  
Marcela Guzman-Ayala ◽  
Kian Leong Lee ◽  
Konstantinos J. Mavrakis ◽  
Paraskevi Goggolidou ◽  
Dominic P. Norris ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Target Gene ◽  
Embryonic Stem ◽  
Target Gene Expression

scholarly journals A UPF1 variant drives conditional remodeling of nonsense-mediated mRNA decay

2021 ◽  
Author(s):  
Sarah E. Fritz ◽  
Soumya Ranganathan ◽  
J. Robert Hogg
Keyword(s):  
Gene Expression ◽  
Mrna Decay ◽  
Gene Expression Regulation ◽  
Translation Termination ◽  
Translational Repression ◽  
The Core ◽  
Human Genes ◽  
Rna Quality Control ◽  
Nonsense Mediated Mrna Decay

AbstractThe nonsense-mediated mRNA decay (NMD) pathway monitors translation termination to degrade transcripts with premature stop codons and regulate thousands of human genes. Due to the major role of NMD in RNA quality control and gene expression regulation, it is important to understand how the pathway responds to changing cellular conditions. Here we show that an alternative mammalian-specific isoform of the core NMD factor UPF1, termed UPF1LL, enables condition-dependent remodeling of NMD specificity. UPF1LL associates more stably with potential NMD target mRNAs than the major UPF1SL isoform, expanding the scope of NMD to include many transcripts normally immune to the pathway. Unexpectedly, the enhanced persistence of UPF1LL on mRNAs supports induction of NMD in response to rare translation termination events. Thus, while canonical NMD is abolished by translational repression, UPF1LL activity is enhanced, providing a mechanism to rapidly rewire NMD specificity in response to cellular stress.

Relief of a repressed gene expression state in the mouse 1-cell embryo requires DNA replication

Development ◽  
1998 ◽  
Vol 125 (16) ◽  
pp. 3153-3166
Author(s):  
S. Forlani ◽  
C. Bonnerot ◽  
S. Capgras ◽  
J.F. Nicolas
Keyword(s):  
Gene Expression ◽  
Dna Replication ◽  
Long Range ◽  
Embryonic Stem ◽  
Hypoxanthine Phosphoribosyl Transferase ◽  
Cell Stage ◽  
Enhancer Activity ◽  
Position Effects ◽  
Cell Proliferation And Differentiation ◽  
Cell Embryo

In the mouse, transcriptional permissiveness is established in the fertilized egg prior to the activation of zygotic genes at the 2-cell stage. Therefore, gene inactivity initiated at the end of gametogenesis results from a complex process, involving more than an inhibition of the basal transcriptional apparatus. We have examined the ability of the first intron (I1) of the human hypoxanthine phosphoribosyl transferase gene, which functions as an enhancer in embryonic stem cells, to activate a reporter gene when placed proximally to or at a distance from the HSV-tk promoter, or when integrated into the mouse genome as part of a stable transgene. In microinjected embryos, I1 functions as an enhancer sequence; however, its competence for long-range activation appears only after the late 1-cell stage and depends on the first DNA replication. Moreover, activation of microinjected transgenes from proximal enhancers occurs in the late 2-cell embryo and in the male pronucleus of 1-cell embryos blocked for DNA replication; whereas, for integrated transgenes, proximal enhancer activity is subject to position effects in the 2-cell embryo and first occurs at the 2- or 4-cell stage, but only after completion of DNA replication. Therefore, the absence of long-range activation and a non-permissive genomic state (the relief of which both depend on DNA replication), together with an inactive transcriptional apparatus, appear to converge to prevent any gene activity in the 1-cell embryo. We propose that the embryo exploits the process of DNA replication to relieve the transcriptionally repressive state that was initially established to fulfil two purposes: (1) to arrest maternal gene expression in the maturing oocyte and (2) to protect the unicellular egg and 1-cell embryo from premature differentiation. Reactivation of gene expression by DNA replication would therefore serve to coordinate cell proliferation and differentiation in the preimplantation embryo.

scholarly journals Direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila

2019 ◽  
Vol 116 (20) ◽  
pp. 9893-9902 ◽  
Author(s):  
Christopher M. Uyehara ◽  
Daniel J. McKay
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Nuclear Receptor ◽  
Binding Sites ◽  
Transcriptional Responses ◽  
Enhancer Activity ◽  
Developmental Transitions ◽  
Experimental Systems ◽  
The Impact

The ecdysone pathway was among the first experimental systems employed to study the impact of steroid hormones on the genome. In Drosophila and other insects, ecdysone coordinates developmental transitions, including wholesale transformation of the larva into the adult during metamorphosis. Like other hormones, ecdysone controls gene expression through a nuclear receptor, which functions as a ligand-dependent transcription factor. Although it is clear that ecdysone elicits distinct transcriptional responses within its different target tissues, the role of its receptor, EcR, in regulating target gene expression is incompletely understood. In particular, EcR initiates a cascade of transcription factor expression in response to ecdysone, making it unclear which ecdysone-responsive genes are direct EcR targets. Here, we use the larval-to-prepupal transition of developing wings to examine the role of EcR in gene regulation. Genome-wide DNA binding profiles reveal that EcR exhibits widespread binding across the genome, including at many canonical ecdysone response genes. However, the majority of its binding sites reside at genes with wing-specific functions. We also find that EcR binding is temporally dynamic, with thousands of binding sites changing over time. RNA-seq reveals that EcR acts as both a temporal gate to block precocious entry to the next developmental stage as well as a temporal trigger to promote the subsequent program. Finally, transgenic reporter analysis indicates that EcR regulates not only temporal changes in target enhancer activity but also spatial patterns. Together, these studies define EcR as a multipurpose, direct regulator of gene expression, greatly expanding its role in coordinating developmental transitions.

Untraditional methods for targeting the kidney in transgenic mice

2003 ◽  
Vol 285 (6) ◽  
pp. F1027-F1033 ◽  
Author(s):  
Robert A. Bianco ◽  
Henry L. Keen ◽  
Julie L. Lavoie ◽  
Curt D. Sigmund
Keyword(s):  
Gene Expression ◽  
Human Genome Project ◽  
Target Gene ◽  
Cell Types ◽  
Experimental Models ◽  
Genome Project ◽  
Renal Physiology ◽  
Physiological Relevance ◽  
The Human Genome Project

With the completion of the human genome project and the sequencing of many genomes of experimental models, there is a pressing need to determine the physiological relevance of newly identified genes. Gene-targeting approaches have become an important tool in our arsenal to dissect the significance of genes expressed in many tissues. A wealth of experimental models has been made to assess the role of gene expression in renal function and development. The development of new and informative models is presently limited by the anatomic complexity of the kidney and the lack of cell-specific promoters to target the numerous diverse cell types in that organ. Because of this, new approaches may have to be developed. In this review, we will discuss several untraditional methods to target gene expression to the kidney. These approaches should provide some additional tricks and tools to help in developing additional informative models for studying renal physiology.

scholarly journals Fatty acids, epigenetic mechanisms and chronic diseases: a systematic review

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
K. González-Becerra ◽  
O. Ramos-Lopez ◽  
E. Barrón-Cabrera ◽  
J. I. Riezu-Boj ◽  
F. I. Milagro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systematic Review ◽  
Fatty Acids ◽  
Chronic Diseases ◽  
Gene Expression Regulation ◽  
Saturated Fatty Acids ◽  
Dietary Fatty Acids ◽  
Epigenetic Mechanisms ◽  
Metabolic Alterations

Abstract Background Chronic illnesses like obesity, type 2 diabetes (T2D) and cardiovascular diseases, are worldwide major causes of morbidity and mortality. These pathological conditions involve interactions between environmental, genetic, and epigenetic factors. Recent advances in nutriepigenomics are contributing to clarify the role of some nutritional factors, including dietary fatty acids in gene expression regulation. This systematic review assesses currently available information concerning the role of the different fatty acids on epigenetic mechanisms that affect the development of chronic diseases or induce protective effects on metabolic alterations. Methods A targeted search was conducted in the PubMed/Medline databases using the keywords “fatty acids and epigenetic”. The data were analyzed according to the PRISMA-P guidelines. Results Consumption fatty acids like n-3 PUFA: EPA and DHA, and MUFA: oleic and palmitoleic acid was associated with an improvement of metabolic alterations. On the other hand, fatty acids that have been associated with the presence or development of obesity, T2D, pro-inflammatory profile, atherosclerosis and IR were n-6 PUFA, saturated fatty acids (stearic and palmitic), and trans fatty acids (elaidic), have been also linked with epigenetic changes. Conclusions Fatty acids can regulate gene expression by modifying epigenetic mechanisms and consequently result in positive or negative impacts on metabolic outcomes.

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