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)

scholarly journals The Role of RNA-Binding Proteins in Vertebrate Neural Crest and Craniofacial Development

2021 ◽  
Vol 9 (3) ◽  
pp. 34
Author(s):  
Thomas E. Forman ◽  
Brenna J. C. Dennison ◽  
Katherine A. Fantauzzo
Keyword(s):  
Gene Expression ◽  
Neural Crest ◽  
Binding Proteins ◽  
Rna Binding ◽  
Gene Expression Regulation ◽  
Rna Binding Proteins ◽  
Craniofacial Development ◽  
Specific Sequence ◽  
Altered Expression ◽  
Binding Domains

Cranial neural crest (NC) cells delaminate from the neural folds in the forebrain to the hindbrain during mammalian embryogenesis and migrate into the frontonasal prominence and pharyngeal arches. These cells generate the bone and cartilage of the frontonasal skeleton, among other diverse derivatives. RNA-binding proteins (RBPs) have emerged as critical regulators of NC and craniofacial development in mammals. Conventional RBPs bind to specific sequence and/or structural motifs in a target RNA via one or more RNA-binding domains to regulate multiple aspects of RNA metabolism and ultimately affect gene expression. In this review, we discuss the roles of RBPs other than core spliceosome components during human and mouse NC and craniofacial development. Where applicable, we review data on these same RBPs from additional vertebrate species, including chicken, Xenopus and zebrafish models. Knockdown or ablation of several RBPs discussed here results in altered expression of transcripts encoding components of developmental signaling pathways, as well as reduced cell proliferation and/or increased cell death, indicating that these are common mechanisms contributing to the observed phenotypes. The study of these proteins offers a relatively untapped opportunity to provide significant insight into the mechanisms underlying gene expression regulation during craniofacial morphogenesis.

FLT3ITD Target Enhancers Are Primed but Inaccessible in Fetal Hematopoietic Progenitors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1228-1228
Author(s):  
Yanan Li ◽  
Riddhi M Patel ◽  
Emily Casey ◽  
Jeffrey A. Magee
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Target Gene ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Gene Activation ◽  
Chromatin Accessibility ◽  
Luciferase Reporter ◽  
Enhancer Activity ◽  
Target Gene Expression

The FLT3 Internal Tandem Duplication (FLT3ITD) is common somatic mutation in acute myeloid leukemia (AML). We have previously shown that FLT3ITD fails to induce changes in HSC self-renewal, myelopoiesis and leukemogenesis during fetal stages of life. FLT3ITD signal transduction pathways are hyperactivated in fetal progenitors, but FLT3ITD target genes are not. This suggests that postnatal-specific transcription factors may be required to help induce FLT3ITD target gene expression. Alternatively, repressive histone modifications may impose a barrier to FLT3ITD target gene activation in fetal HPCs that is relaxed during postnatal development. To resolve these possibilities, we used ATAC-seq, as well as H3K4me1, H3K27ac and H3K27me3 ChIP-seq, to identify cis-elements that putatively control FLT3ITD target gene expression in fetal and adult hematopoietic progenitor cells (HPCs). We identified many enhancer elements (ATAC-seq peaks with H3K4me1 and H3K27ac) that exhibited increased chromatin accessibility and activity in FLT3ITD adult HPCs relative to wild type adult HPCs. These elements were enriched near FLT3ITD target genes. HOMER analysis showed enrichment for STAT5, ETS, RUNX1 and IRF binding motifs within the FLT3ITD target enhancers, but motifs for temporally dynamic transcription factors were not identified. We cloned a subset of the enhancers and confirmed that they could synergize with their promoter to activate a luciferase reporter. For representative enhancers, STAT5 binding sites were required to activate the enhancer - as anticipated - and RUNX1 repressed enhancer activity. We tested whether accessibility or priming changed between fetal and adult stages of HPC development. FLT3ITD-dependent changes in chromatin accessibility were not observed in fetal HPCs, though the enhancers were primed early in development as evidenced by the presence of H3K4me1. Repressive H3K27me3 were not present at FLT3ITD target enhancers in either or adult HPCs. The data show that FLT3ITD target enhancers are demarcated early in hematopoietic development, long before they become responsive to FLT3ITD signaling. Repressive marks do not appear to create an epigenetic barrier to enhancer activation in the fetal stage. Instead, age-specific transcription factors are likely required to pioneer enhancer elements so that they can respond to STAT5 and other FLT3ITD effectors. Disclosures No relevant conflicts of interest to declare.

scholarly journals MicroRNA-Mediated Responses to Cadmium Stress in Arabidopsis thaliana

Plants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 130
Author(s):  
Joseph L. Pegler ◽  
Jackson M. J. Oultram ◽  
Duc Quan Nguyen ◽  
Christopher P. L. Grof ◽  
Andrew L. Eamens
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Mirna Target ◽  
Target Gene ◽  
Rna Binding ◽  
Molecular Response ◽  
Cd Stress ◽  
Mirna Target Gene ◽  
Target Gene Expression ◽  
Essential Heavy Metal

In recent decades, the presence of cadmium (Cd) in the environment has increased significantly due to anthropogenic activities. Cd is taken up from the soil by plant roots for its subsequent translocation to shoots. However, Cd is a non-essential heavy metal and is therefore toxic to plants when it over-accumulates. MicroRNA (miRNA)-directed gene expression regulation is central to the response of a plant to Cd stress. Here, we document the miRNA-directed response of wild-type Arabidopsis thaliana (Arabidopsis) plants and the drb1, drb2 and drb4 mutant lines to Cd stress. Phenotypic and physiological analyses revealed the drb1 mutant to display the highest degree of tolerance to the imposed stress while the drb2 mutant was the most sensitive. RT-qPCR-based molecular profiling of miRNA abundance and miRNA target gene expression revealed DRB1 to be the primary double-stranded RNA binding (DRB) protein required for the production of six of the seven Cd-responsive miRNAs analyzed. However, DRB2, and not DRB1, was determined to be required for miR396 production. RT-qPCR further inferred that transcript cleavage was the RNA silencing mechanism directed by each assessed miRNA to control miRNA target gene expression. Taken together, the results presented here reveal the complexity of the miRNA-directed molecular response of Arabidopsis to Cd stress.

scholarly journals The Role of lncRNAs in Gene Expression Regulation through mRNA Stabilization

2021 ◽  
Vol 7 (1) ◽  
pp. 3
Author(s):  
Maialen Sebastian-delaCruz ◽  
Itziar Gonzalez-Moro ◽  
Ane Olazagoitia-Garmendia ◽  
Ainara Castellanos-Rubio ◽  
Izortze Santin
Keyword(s):  
Gene Expression ◽  
Mrna Stability ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Gene Expression Regulation ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Mrna Stabilization ◽  
Living Organisms ◽  
Almost All

mRNA stability influences gene expression and translation in almost all living organisms, and the levels of mRNA molecules in the cell are determined by a balance between production and decay. Maintaining an accurate balance is crucial for the correct function of a wide variety of biological processes and to maintain an appropriate cellular homeostasis. Long non-coding RNAs (lncRNAs) have been shown to participate in the regulation of gene expression through different molecular mechanisms, including mRNA stabilization. In this review we provide an overview on the molecular mechanisms by which lncRNAs modulate mRNA stability and decay. We focus on how lncRNAs interact with RNA binding proteins and microRNAs to avoid mRNA degradation, and also on how lncRNAs modulate epitranscriptomic marks that directly impact on mRNA stability.

scholarly journals MicroRNA Maturation and MicroRNA Target Gene Expression Regulation Are Severely Disrupted in Soybean dicer-like1 Double Mutants

2015 ◽  
Vol 6 (2) ◽  
pp. 423-433 ◽  
Author(s):  
Shaun J. Curtin ◽  
Jean-Michel Michno ◽  
Benjamin W. Campbell ◽  
Javier Gil-Humanes ◽  
Sandra M. Mathioni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Gene Expression Regulation ◽  
Expression Regulation ◽  
Microrna Target ◽  
Target Gene Expression

scholarly journals Computational Methods for CLIP-Seq Data Processing

2014 ◽  
Vol 8 ◽  
pp. BBI.S16803 ◽  
Author(s):  
Paula H. Reyes-Herrera ◽  
Elisa Ficarra
Keyword(s):  
Gene Expression ◽  
Computational Methods ◽  
High Throughput Sequencing ◽  
Rna Binding ◽  
Gene Expression Regulation ◽  
Rna Binding Proteins ◽  
Current Status ◽  
Gene Expression Control ◽  
Wide Scale ◽  
Interaction Regions

RNA-binding proteins (RBPs) are at the core of post-transcriptional regulation and thus of gene expression control at the RNA level. One of the principal challenges in the field of gene expression regulation is to understand RBPs mechanism of action. As a result of recent evolution of experimental techniques, it is now possible to obtain the RNA regions recognized by RBPs on a transcriptome-wide scale. In fact, CLIP-seq protocols use the joint action of CLIP, crosslinking immunoprecipitation, and high-throughput sequencing to recover the transcriptome-wide set of interaction regions for a particular protein. Nevertheless, computational methods are necessary to process CLIP-seq experimental data and are a key to advancement in the understanding of gene regulatory mechanisms. Considering the importance of computational methods in this area, we present a review of the current status of computational approaches used and proposed for CLIP-seq data.

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 The Biomarker and Therapeutic Potential of Circular Rnas in Schizophrenia

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2238
Author(s):  
Artem Nedoluzhko ◽  
Natalia Gruzdeva ◽  
Fedor Sharko ◽  
Sergey Rastorguev ◽  
Natalia Zakharova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Binding ◽  
Gene Expression Regulation ◽  
Rna Binding Proteins ◽  
Therapeutic Potential ◽  
Expression Patterns ◽  
Circular Rna ◽  
Circular Rnas ◽  
Cellular Processes ◽  
Non Coding Rna

Circular RNAs (circRNAs) are endogenous, single-stranded, most frequently non-coding RNA (ncRNA) molecules that play a significant role in gene expression regulation. Circular RNAs can affect microRNA functionality, interact with RNA-binding proteins (RBPs), translate proteins by themselves, and directly or indirectly modulate gene expression during different cellular processes. The affected expression of circRNAs, as well as their targets, can trigger a cascade of events in the genetic regulatory network causing pathological conditions. Recent studies have shown that altered circular RNA expression patterns could be used as biomarkers in psychiatric diseases, including schizophrenia (SZ); moreover, circular RNAs together with other cell molecules could provide new insight into mechanisms of this disorder. In this review, we focus on the role of circular RNAs in the pathogenesis of SZ and analyze their biomarker and therapeutic potential in this disorder.

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.

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