scholarly journals A revised model for promoter competition based on multi-way chromatin interactions

2019 ◽  
Author(s):  
A. Marieke Oudelaar ◽  
Caroline L. Harrold ◽  
Lars L. P. Hanssen ◽  
Jelena M. Telenius ◽  
Douglas R. Higgs ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Chromatin Domain ◽  
Gene Promoters ◽  
Multiple Promoters ◽  
Chromatin Interactions ◽  
Super Enhancer ◽  
Technological Advances ◽  
Single Complex

AbstractSpecific communication between gene promoters and enhancers is critical for accurate regulation of gene expression. However, it remains unclear how specific interactions between multiple regulatory elements and genes contained within a single chromatin domain are coordinated. Recent technological advances allow for the investigation of multi-way chromatin interactions at single alleles in individual nuclei. This can provide insights into how multiple regulatory elements cooperate or compete for transcriptional activation. We have used these techniques in a mouse model in which the α-globin domain is extended to include several additional genes. This allows us to determine how the interactions of the α-globin super-enhancer are distributed between multiple promoters in a single domain. Our data show that gene promoters do not form mutually exclusive interactions with the super-enhancer, but all interact simultaneously in a single complex. These finding show that promoters within the same domain do not structurally compete for interactions with enhancers, but form a regulatory hub structure, consistent with the recent model of transcriptional activation in phase-separated nuclear condensates.

scholarly journals A revised model for promoter competition based on multi-way chromatin interactions at the α-globin locus

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
A. Marieke Oudelaar ◽  
Caroline L. Harrold ◽  
Lars L. P. Hanssen ◽  
Jelena M. Telenius ◽  
Douglas R. Higgs ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Chromatin Domain ◽  
Gene Promoters ◽  
Multiple Promoters ◽  
Chromatin Interactions ◽  
Technological Advances ◽  
Single Complex ◽  
Membrane Bound

AbstractSpecific communication between gene promoters and enhancers is critical for accurate regulation of gene expression. However, it remains unclear how specific interactions between multiple regulatory elements contained within a single chromatin domain are coordinated. Recent technological advances which can detect multi-way chromatin interactions at single alleles can provide insights into how multiple regulatory elements cooperate or compete for transcriptional activation. Here, we use such an approach to investigate how interactions of the α-globin enhancers are distributed between multiple promoters in a mouse model in which the α-globin domain is extended to include several additional genes. Our data show that gene promoters do not form mutually exclusive interactions with enhancers, but all interact simultaneously in a single complex. These findings suggest that promoters do not structurally compete for interactions with enhancers, but form a regulatory hub structure, which is consistent with recent models of transcriptional activation occurring in non-membrane bound nuclear compartments.

scholarly journals Glucocorticoid receptor wields chromatin interactions to tune transcription for cytoskeleton stabilization in podocytes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hong Wang ◽  
Aiping Duan ◽  
Jing Zhang ◽  
Qi Wang ◽  
Yuexian Xing ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Glucocorticoid Receptor ◽  
Protective Effect ◽  
Histone Modification ◽  
Regulatory Networks ◽  
Target Gene ◽  
Regulatory Elements ◽  
Chromatin Interactions ◽  
Super Enhancer

AbstractElucidating transcription mediated by the glucocorticoid receptor (GR) is crucial for understanding the role of glucocorticoids (GCs) in the treatment of diseases. Podocyte is a useful model for studying GR regulation because GCs are the primary medication for podocytopathy. In this study, we integrated data from transcriptome, transcription factor binding, histone modification, and genome topology. Our data reveals that the GR binds and activates selective regulatory elements in podocyte. The 3D interactome captured by HiChIP facilitates the identification of remote targets of GR. We found that GR in podocyte is enriched at transcriptional interaction hubs and super-enhancers. We further demonstrate that the target gene of the top GR-associated super-enhancer is indispensable to the effective functioning of GC in podocyte. Our findings provided insights into the mechanisms underlying the protective effect of GCs on podocyte, and demonstrate the importance of considering transcriptional interactions in order to fine-map regulatory networks of GR.

scholarly journals Virus-Dependent Phosphorylation of the IRF-3 Transcription Factor Regulates Nuclear Translocation, Transactivation Potential, and Proteasome-Mediated Degradation

1998 ◽  
Vol 18 (5) ◽  
pp. 2986-2996 ◽  
Author(s):  
Rongtuan Lin ◽  
Christophe Heylbroeck ◽  
Paula M. Pitha ◽  
John Hiscott
Keyword(s):  
Virus Infection ◽  
Transcriptional Activation ◽  
Nuclear Translocation ◽  
Sendai Virus ◽  
Active Form ◽  
Proteasome Inhibitors ◽  
Point Mutations ◽  
Regulatory Elements ◽  
Gene Promoters ◽  
Creb Binding Protein

ABSTRACT The interferon regulatory factors (IRF) consist of a growing family of related transcription proteins first identified as regulators of the alpha beta interferon (IFN-α/β) gene promoters, as well as the interferon-stimulated response element (ISRE) of some IFN-stimulated genes. IRF-3 was originally identified as a member of the IRF family based on homology with other IRF family members and on binding to the ISRE of the ISG15 promoter. IRF-3 is expressed constitutively in a variety of tissues, and the relative levels of IRF-3 mRNA do not change in virus-infected or IFN-treated cells. In the present study, we demonstrate that following Sendai virus infection, IRF-3 is posttranslationally modified by protein phosphorylation at multiple serine and threonine residues, which are located in the carboxy terminus of IRF-3. A combination of IRF-3 deletion and point mutations localized the inducible phosphorylation sites to the region -ISNSHPLSLTSDQ- between amino acids 395 and 407; point mutation of residues Ser-396 and Ser-398 eliminated virus-induced phosphorylation of IRF-3 protein, although residues Ser-402, Thr-404, and Ser-405 were also targets. Phosphorylation results in the cytoplasm-to-nucleus translocation of IRF-3, DNA binding, and increased transcriptional activation. Substitution of the Ser-Thr sites with the phosphomimetic Asp generated a constitutively active form of IRF-3 that functioned as a very strong activator of promoters containing PRDI-PRDIII or ISRE regulatory elements. Phosphorylation also appears to represent a signal for virus-mediated degradation, since the virus-induced turnover of IRF-3 was prevented by mutation of the IRF-3 Ser-Thr cluster or by proteasome inhibitors. Interestingly, virus infection resulted in the association of IRF-3 with the CREB binding protein (CBP) coactivator, as detected by coimmunoprecipitation with anti-CBP antibody, an interaction mediated by the C-terminal domains of both proteins. Mutation of residues Ser-396 and Ser-398 in IRF-3 abrogated its binding to CBP. These results are discussed in terms of a model in which virus-inducible, C-terminal phosphorylation of IRF-3 alters protein conformation to permit nuclear translocation, association with transcriptional partners, and primary activation of IFN- and IFN-responsive genes.

scholarly journals CREAM: Clustering of genomic REgions Analysis Method

2017 ◽  
Author(s):  
Seyed Ali Madani Tonekaboni ◽  
Parisa Mazrooei ◽  
Victor Kofia ◽  
Benjamin Haibe-Kains ◽  
Mathieu Lupien
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
R Package ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Analysis Method ◽  
Chromatin Interactions ◽  
Super Enhancer ◽  
Highly Expressed Genes ◽  
Genomic Regions

ABSTRACTCellular identity relies on cell type-specific gene expression profiles controlled by cis-regulatory elements (CREs), such as promoters, enhancers and anchors of chromatin interactions. CREs are unevenly distributed across the genome, giving rise to distinct subsets such as individual CREs and Clusters Of cis-Regulatory Elements (COREs), also known as super-enhancers. Identifying COREs is a challenge due to technical and biological features that entail variability in the distribution of distances between CREs within a given dataset. To address this issue, we developed a new unsupervised machine learning approach termed Clustering of genomic REgions Analysis Method (CREAM) that outperforms the Ranking Of Super Enhancer (ROSE) approach. Specifically CREAM identified COREs are enriched in CREs strongly bound by master transcription factors according to ChIP-seq signal intensity, are proximal to highly expressed genes, are preferentially found near genes essential for cell growth and are more predictive of cell identity. Moreover, we show that CREAM enables subtyping primary prostate tumor samples according to their CORE distribution across the genome. We further show that COREs are enriched compared to individual CREs at TAD boundaries and these are preferentially bound by CTCF and factors of the cohesin complex (e.g.: RAD21 and SMC3). Finally, using CREAM against transcription factor ChIP-seq reveals CTCF and cohesin-specific COREs preferentially at TAD boundaries compared to intra-TADs. CREAM is available as an open source R package (https://CRAN.R-project.org/package=CREAM) to identify COREs from cis-regulatory annotation datasets from any biological samples.

scholarly journals The transcription factor GLI1 cooperates with the chromatin remodeler SMARCA2 to regulate chromatin accessibility at distal DNA regulatory elements

2020 ◽  
Vol 295 (26) ◽  
pp. 8725-8735
Author(s):  
Stephanie L. Safgren ◽  
Rachel L. O. Olson ◽  
Anne M. Vrabel ◽  
Luciana L. Almada ◽  
David L. Marks ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activation ◽  
Transcriptional Activity ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Micrococcal Nuclease ◽  
Gene Promoters ◽  
Interacting Protein ◽  
Transcriptional Activation Domain ◽  
Dna Regulatory Elements

The transcription factor GLI1 (GLI family zinc finger 1) plays a key role in the development and progression of multiple malignancies. To date, regulation of transcriptional activity at target gene promoters is the only molecular event known to underlie the oncogenic function of GLI1. Here, we provide evidence that GLI1 controls chromatin accessibility at distal regulatory regions by modulating the recruitment of SMARCA2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2) to these elements. We demonstrate that SMARCA2 endogenously interacts with GLI1 and enhances its transcriptional activity. Mapping experiments indicated that the C-terminal transcriptional activation domain of GLI1 and SMARCA2's central domains, including its ATPase motif, are required for this interaction. Interestingly, similar to SMARCA2, GLI1 overexpression increased chromatin accessibility, as indicated by results of the micrococcal nuclease assay. Further, results of assays for transposase-accessible chromatin with sequencing (ATAC-seq) after GLI1 knockdown supported these findings, revealing that GLI1 regulates chromatin accessibility at several regions distal to gene promoters. Integrated RNA-seq and ATAC-seq data analyses identified a subset of differentially expressed genes located in cis to these regulated chromatin sites. Finally, using the GLI1-regulated gene HHIP (Hedgehog-interacting protein) as a model, we demonstrate that GLI1 and SMARCA2 co-occupy a distal chromatin peak and that SMARCA2 recruitment to this HHIP putative enhancer requires intact GLI1. These findings provide insights into how GLI1 controls gene expression in cancer cells and may inform approaches targeting this oncogenic transcription factor to manage malignancies.

scholarly journals Dempster-Shafer Theory for the Prediction of Auxin-Response Elements (AuxREs) in Plant Genomes

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Nesrine Sghaier ◽  
Rayda Ben Ayed ◽  
Riadh Ben Marzoug ◽  
Ahmed Rebai
Keyword(s):  
Data Fusion ◽  
Transcriptional Activation ◽  
False Positive ◽  
Fuzzy Theory ◽  
Regulation Of Gene Expression ◽  
Evidence Theory ◽  
Regulatory Elements ◽  
Auxin Response ◽  
Shafer Theory ◽  
Comparison Of The Results

Auxin is a major regulator of plant growth and development; its action involves transcriptional activation. The identification of Auxin-response element (AuxRE) is one of the most important issues to understand the Auxin regulation of gene expression. Over the past few years, a large number of motif identification tools have been developed. Despite these considerable efforts provided by computational biologists, building reliable models to predict regulatory elements has still been a difficult challenge. In this context, we propose in this work a data fusion approach for the prediction of AuxRE. Our method is based on the combined use of Dempster-Shafer evidence theory and fuzzy theory. To evaluate our model, we have scanning the DORNRÖSCHEN promoter by our model. All proven AuxRE present in the promoter has been detected. At the 0.9 threshold we have no false positive. The comparison of the results of our model and some previous motifs finding tools shows that our model can predict AuxRE more successfully than the other tools and produce less false positive. The comparison of the results before and after combination shows the importance of Dempster-Shafer combination in the decrease of false positive and to improve the reliability of prediction. For an overall evaluation we have chosen to present the performance of our approach in comparison with other methods. In fact, the results indicated that the data fusion method has the highest degree of sensitivity (Sn) and Positive Predictive Value (PPV).

scholarly journals C3D: A tool to predict 3D genomic interactions between cis-regulatory elements

2017 ◽  
Author(s):  
Tahmid Mehdi ◽  
Swneke D. Bailey ◽  
Paul Guilhamon ◽  
Mathieu Lupien
Keyword(s):  
Regulatory Elements ◽  
Gene Promoters ◽  
Cell Type ◽  
Computational Tool ◽  
3D Genome ◽  
Dna Accessibility ◽  
Chromatin Interactions ◽  
Hypersensitive Sites ◽  
R Packages ◽  
Mcf 7

ABSTRACTMotivationThe 3D genome architecture influences the regulation of genes by facilitating chromatin interactions between distal cis-regulatory elements and gene promoters. We implement Cross Cell-type Correlation based on DNA accessibility (C3D), a highly customizable computational tool that predicts chromatin interactions using an unsupervised algorithm that utilizes correlations in chromatin measurements, such as DNaseI hypersensitivity signals.ResultsC3D accurately predicts 32.7%, 18.3% and 24.1% of interactions, validated by ChIA-PET assays, between promoters and distal regions that overlie DNaseI hypersensitive sites in K562, MCF-7 and GM12878 cells, respectively.AvailabilitySource code is open-source and freely available on GitHub (https://github.com/LupienLabOrganization/C3D) under the GNU GPLv3 license. C3D is implemented in Bash and R; it runs on any platform with Bash (≥4.0), R (≥3.1.1) and BEDTools (≥2.19.0). It requires the following R packages: GenomicRanges, Sushi, data.table, preprocessCore and dynamicTreeCut.

scholarly journals SEA version 3.0: a comprehensive extension and update of the Super-Enhancer archive

2019 ◽  
Author(s):  
Chuangeng Chen ◽  
Dianshuang Zhou ◽  
Yue Gu ◽  
Cong Wang ◽  
Mengyan Zhang ◽  
...  
Keyword(s):  
Regulation Of Gene Expression ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Cell Type Specificity ◽  
Chromatin Interactions ◽  
Super Enhancer ◽  
Genome Visualization ◽  
Multiple Species ◽  
New Criteria ◽  
Query Genome

Abstract Super-enhancers (SEs) are critical for the transcriptional regulation of gene expression. We developed the super-enhancer archive version 3.0 (SEA v. 3.0, http://sea.edbc.org) to extend SE research. SEA v. 3.0 provides the most comprehensive archive to date, consisting of 164 545 super-enhancers. Of these, 80 549 are newly identified from 266 cell types/tissues/diseases using an optimized computational strategy, and 52 have been experimentally confirmed with manually curated references. We now support super-enhancers in 11 species including 7 new species (zebrafish, chicken, chimp, rhesus, sheep, Xenopus tropicalis and stickleback). To facilitate super-enhancer functional analysis, we added several new regulatory datasets including 3 361 785 typical enhancers, chromatin interactions, SNPs, transcription factor binding sites and SpCas9 target sites. We also updated or developed new criteria query, genome visualization and analysis tools for the archive. This includes a tool based on Shannon Entropy to evaluate SE cell type specificity, a new genome browser that enables the visualization of SE spatial interactions based on Hi-C data, and an enhanced enrichment analysis interface that provides online enrichment analyses of SE related genes. SEA v. 3.0 provides a comprehensive database of all available SE information across multiple species, and will facilitate super-enhancer research, especially as related to development and disease.

scholarly journals In Silico Analysis of Osa-miR164 Gene Family in Rice (Oryza Sativa)

2021 ◽  
Vol 37 (3) ◽  
Author(s):  
Vuong Quang Tien ◽  
Nguyen Huy Duong ◽  
Dao Trong Nhan ◽  
Phan Minh Vu ◽  
Do Thi Phuc
Keyword(s):  
Oryza Sativa ◽  
Expression Pattern ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
In Silico Analysis ◽  
Regulatory Elements ◽  
Stress Conditions ◽  
Gene Promoters ◽  
Non Coding Rna ◽  
Post Transcriptional Regulation

MicroRNA (miRNA) is a small non-coding RNA molecule containing about 22- 24 nucleotides, which functions in post-transcriptional regulation of gene expression. Previous reports have shown that miRNA plays an important role on the resistance ability of plants to adverse conditions. Rice (Oryza sativa) is a major food crop. Climate change makes the situation of salinity and drought in Vietnam worse, significantly affects rice cultivation area, leading to the decrease of the quantity and the quality of rice grains. In this research, we focused on miR164 family in rice. By using bioinformatics approach, we analyzed sequences of all osa-miR164 belonging to rice miR164 family, evaluated the expression profile of osa-miR164 under different stress conditions, predicted cis-regulatory elements on osa-miR164 gene promoters, and simultaneously predicted miR164-targeted genes and their expressions. The results showed the high conserve in mature osa-miR164 sequences but not in the precursor sequences, different expression pattern of osa-miR164 gene members under stress conditions and various cis-regulatory elements present in osa-miR164 gene promoters which may explain for diverse expression pattern of osa-miR164 genes. Some potential target genes of osa-miR164 were identified and their expressions under different stress conditions were analyzed.

scholarly journals Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma

Gut ◽  
2019 ◽  
Vol 69 (4) ◽  
pp. 630-640 ◽  
Author(s):  
Li Chen ◽  
Moli Huang ◽  
Jasmine Plummer ◽  
Jian Pan ◽  
Yan Yi Jiang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Oesophageal Cancer ◽  
Transcriptional Activation ◽  
Regulatory Elements ◽  
Luciferase Assay ◽  
Oesophageal Adenocarcinoma ◽  
Transcriptional Networks ◽  
Specific Gene ◽  
Super Enhancer

ObjectiveWhile oesophageal squamous cell carcinoma remains infrequent in Western populations, the incidence of oesophageal adenocarcinoma (EAC) has increased sixfold to eightfold over the past four decades. We aimed to characterise oesophageal cancer-specific and subtypes-specific gene regulation patterns and their upstream transcription factors (TFs). DesignTo identify regulatory elements, we profiled fresh-frozen oesophageal normal samples, tumours and cell lines with chromatin immunoprecipitation sequencing (ChIP-Seq). Mathematical modelling was performed to establish (super)-enhancers landscapes and interconnected transcriptional circuitry formed by master TFs. Coregulation and cooperation between master TFs were investigated by ChIP-Seq, circularised chromosome conformation capture sequencing and luciferase assay. Biological functions of candidate factors were evaluated both in vitro and in vivo.ResultsWe found widespread and pervasive alterations of the (super)-enhancer reservoir in both subtypes of oesophageal cancer, leading to transcriptional activation of a myriad of novel oncogenes and signalling pathways, some of which may be exploited pharmacologically (eg, leukemia inhibitory factor (LIF) pathway). Focusing on EAC, we bioinformatically reconstructed and functionally validated an interconnected circuitry formed by four master TFs—ELF3, KLF5, GATA6 and EHF—which promoted each other’s expression by interacting with each super-enhancer. Downstream, these master TFs occupied almost all EAC super-enhancers and cooperatively orchestrated EAC transcriptome. Each TF within the transcriptional circuitry was highly and specifically expressed in EAC and functionally promoted EAC cell proliferation and survival.ConclusionsBy establishing cancer-specific and subtype-specific features of the EAC epigenome, our findings promise to transform understanding of the transcriptional dysregulation and addiction of EAC, while providing molecular clues to develop novel therapeutic modalities against this malignancy.

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