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 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.

Spatially specific expression of Hoxb4 is dependent on the ubiquitous transcription factor NFY

Development ◽  
2002 ◽  
Vol 129 (16) ◽  
pp. 3887-3899 ◽  
Author(s):  
Jonathan Gilthorpe ◽  
Marie Vandromme ◽  
Tim Brend ◽  
Alejandro Gutman ◽  
Dennis Summerbell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Sites ◽  
Specific Interaction ◽  
Transcriptional Regulators ◽  
Heterologous Promoter ◽  
Specific Expression ◽  
Enhancer Activity ◽  
Hox Gene ◽  
Two Factors ◽  
Enhancer Function

Understanding how boundaries and domains of Hox gene expression are determined is critical to elucidating the means by which the embryo is patterned along the anteroposterior axis. We have performed a detailed analysis of the mouse Hoxb4 intron enhancer to identify upstream transcriptional regulators. In the context of an heterologous promoter, this enhancer can establish the appropriate anterior boundary of mesodermal expression but is unable to maintain it, showing that a specific interaction with its own promoter is important for maintenance. Enhancer function depends on a motif that contains overlapping binding sites for the transcription factors NFY and YY1. Specific mutations that either abolish or reduce NFY binding show that it is crucial for enhancer activity. The NFY/YY1 motif is reiterated in the Hoxb4 promoter and is known to be required for its activity. As these two factors are able to mediate opposing transcriptional effects by reorganizing the local chromatin environment, the relative levels of NFY and YY1 binding could represent a mechanism for balancing activation and repression of Hoxb4 through the same site.

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 Analysis of Genes That Encode DtxR-Like Transcriptional Regulators in Pathogenic and Saprophytic Corynebacterial Species

2004 ◽  
Vol 72 (4) ◽  
pp. 1885-1895 ◽  
Author(s):  
Diana Marra Oram ◽  
Ana Avdalovic ◽  
Randall K. Holmes
Keyword(s):  
Gene Expression ◽  
Metal Binding ◽  
Regulatory Protein ◽  
Transcriptional Regulators ◽  
Chromosomal Dna ◽  
Regulate Gene Expression ◽  
Protein Levels ◽  
Diphtheria Toxin Repressor ◽  
Conserved Region ◽  
High Level

ABSTRACT Metal-dependent transcriptional regulators of the diphtheria toxin repressor (DtxR) family have been identified in a wide variety of bacterial genera, where they control gene expression in response to one of two metal ions, Fe2+ or Mn2+. DtxR of Corynebacterium diphtheriae is the best characterized of these important metal-dependent regulators. The genus Corynebacterium includes many phenotypically diverse species, and the prevalence of DtxR-like regulators within the genus is unknown. We assayed chromosomal DNA from 42 different corynebacterial isolates, representing 33 different species, for the presence of a highly conserved region of the dtxR gene that encodes the DNA-binding helix-turn-helix motif and metal-binding site 1 within domains 1 and 2 of DtxR. The chromosome of all of the isolates contained this conserved region of dtxR, and DNA sequencing revealed a high level of nucleotide sequence conservation within this region in all of the corynebacterial species (ranging from 62 to 100% identity and averaging 70% identity with the dtxR prototype). The level of identity was even greater for the predicted protein sequences encoded by the dtxR-like genes, ranging from 81 to 100% identity and averaging 91% identity with DtxR. Using a DtxR-specific antiserum we confirmed the presence of a DtxR-like protein in extracts of most of the corynebacterial isolates and determined the precise amount of DtxR per cell in C. diphtheriae. The high level of identity at both DNA and protein levels suggests that all of the isolates tested encode a functional DtxR-like Fe2+-activated regulatory protein that can bind homologs of the DtxR operator and regulate gene expression in response to iron.

scholarly journals An Arabidopsis gene expression predictor enables inference of transcriptional regulators

2020 ◽  
Author(s):  
Haiying Geng ◽  
Meng Wang ◽  
Jiazhen Gong ◽  
Yupu Xu ◽  
Shisong Ma
Keyword(s):  
Gene Expression ◽  
Lateral Root ◽  
Secondary Cell Wall ◽  
Target Genes ◽  
Gene Expression Regulation ◽  
Transcriptional Regulators ◽  
Endoplasmic Reticulum Stress Response ◽  
Rna Seq ◽  
Average Correlation ◽  
Cell Wall Development

ABSTRACTGene expression regulation by transcription factors (TF) has long been studied, but no model exists yet that can accurately predict transcriptome profiles based on TF activities. We have constructed a universal predictor for Arabidopsis to predict the expression of 28192 non-TF genes using 1678 TFs. Applied to bulk RNA-Seq samples from diverse tissues, the predictor produced accurate predicted transcriptomes correlating well with actual expression, with average correlation coefficient of 0.986. Having recapitulated the quantitative relationships between TFs and target genes, the predictor further enabled downstream inference of TF regulators for genes and pathways, i.e. those involved in suberin, flavonoid, glucosinolate metabolism, lateral root, xylem, secondary cell wall development, and endoplasmic reticulum stress response. Our predictor provides an innovative approach to study transcriptional regulation.

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.

Variants in miRNA regulome and their association with the risk of nonsyndromic orofacial clefts

Epigenomics ◽  
2020 ◽  
Vol 12 (13) ◽  
pp. 1109-1121
Author(s):  
Guirong Zhu ◽  
Chi Zhang ◽  
Yuting Wang ◽  
Yuli Wang ◽  
Dandan Li ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Cleft Lip ◽  
Target Gene ◽  
Luciferase Activity ◽  
Nucleotide Polymorphisms ◽  
Activity Assay ◽  
Orofacial Clefts ◽  
Enhancer Activity ◽  
Single Nucleotide ◽  
Luciferase Activity Assay

Aim: To investigate the associations between single nucleotide polymorphisms (SNPs) in miRNA regulome and nonsyndromic orofacial clefts. Materials & methods: The associations were evaluated by logistic regression model in stage I (504 cases and 455 controls) and stage II (1500 cases and 1386 controls). Functional experiments including luciferase activity assay, cell apoptosis and proliferation, serum miRNA expression, and mouse embryo RNA sequencing were performed. Results: Rs3830766 in the enhancer of hsa-miR-4260 was associated with cleft lip only (CLO) and enhancer activity. Hsa-miR-4260 expression decreased in the serum of CLO. Overexpression of miR-4260 inhibited cell proliferation and promoted cell apoptosis. UBB was the target gene of hsa-miR-4260. Conclusion: Rs3830766 in the hsa-miR-4260 enhancer that can interact with UBB was relevant to CLO.

Finding of IFNγ gene enhancers and their core sequences

Genome ◽  
2013 ◽  
Vol 56 (3) ◽  
pp. 147-154 ◽  
Author(s):  
Zhanjun Lv ◽  
Jianjun Cheng ◽  
Ying Xie ◽  
Xiangyang Jing ◽  
Yuan Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Reporter Gene ◽  
Gene Expression Regulation ◽  
Expression Regulation ◽  
Enhancer Activity ◽  
Gfp Gene ◽  
Gfp Reporter ◽  
Segmentation Methods ◽  
Gfp Reporter Gene ◽  
Dna Segmentation

DNA segmentation methods were used to study which fragments of the human IFNγ gene possess enhancer activity. The human IFNγ gene was divided into 240-bp fragments, which were inserted between the GFP gene and the Alu tandem sequence to determine whether the inserted sequences eliminate the inhibition induced by the Alu tandem sequence. We found that five different 240-bp fragments (FUIFN3F3R, IFN4F4R, IFN6F6R, IFN21F21R, and IFN22F22R) and two 60-bp core sequences (IFN6-2F2R and IFN21-3-4F3-4R) derived from the IFNγ gene contain enhancers that can activate the GFP reporter gene. These enhancers may be targets of IFNγ gene expression regulation.

Sign in / Sign up

Export Citation Format

Share Document