scholarly journals EnhFFL: A database of enhancer mediated feed-forward loops for human and mouse

2021 ◽  
Author(s):  
Ran Kang ◽  
Zhengtang Tan ◽  
Mei Lang ◽  
Linqi Jin ◽  
Yin Zhang ◽  
...  
Keyword(s):  
Mirna Target ◽  
Target Genes ◽  
Mirna Gene ◽  
Regulatory Elements ◽  
Functional Enrichment ◽  
Tissue Cell ◽  
Feed Forward ◽  
Data Resource ◽  
Super Enhancer ◽  
Human And Mouse

Abstract Feed-forward loops (FFLs) are to be one of the most common and important classes of transcriptional network motifs that involved in various diseases. Enhancers are cis-regulatory elements that positively regulate protein-coding genes or microRNAs (miRNAs) by recruiting DNA-binding transcription factors (TFs). However, a comprehensive resource to identify, store and analyze the FFLs of typical enhancer and super-enhancer FFLs is not currently available. Here, we present EnhFFL, an online database to provide a data resource for users to browse and search typical enhancer and super-enhancer FFLs. The current database covers 46,280/7,000 TF-enhancer-miRNA FFLs, 9,997/236 enhancer-miRNA-gene FFLs, 3,561,164/3,193,182 TF-enhancer-gene FFLs and 1,259/235 TF-enhancer feed-back loops (FBLs) across 91 tissues/cell lines of human and mouse, respectively. Users can browse loops by selecting species, types of tissue/cell line and types of FFLs. EnhFFL supports searching elements including name/ID, genomic location and the conservation of miRNA target genes. We also developed tools for users to screen customized FFLs using the threshold of q value as well as the confidence score of miRNA target genes. Disease and functional enrichment analysis showed that master miRNAs that are widely engaged in FFLs including TF-enhancer-miRNAs and enhancer-miRNA-genes significantly involved in tumorigenesis. Database URL: http://lcbb.swjtu.edu.cn/EnhFFL/.

scholarly journals Cistrome-GO: a web server for functional enrichment analysis of transcription factor ChIP-seq peaks

2019 ◽  
Vol 47 (W1) ◽  
pp. W206-W211 ◽  
Author(s):  
Shaojuan Li ◽  
Changxin Wan ◽  
Rongbin Zheng ◽  
Jingyu Fan ◽  
Xin Dong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Transcription Factor ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Differential Gene ◽  
Direct Target ◽  
Human And Mouse

AbstractCharacterizing the ontologies of genes directly regulated by a transcription factor (TF), can help to elucidate the TF’s biological role. Previously, we developed a widely used method, BETA, to integrate TF ChIP-seq peaks with differential gene expression (DGE) data to infer direct target genes. Here, we provide Cistrome-GO, a website implementation of this method with enhanced features to conduct ontology analyses of gene regulation by TFs in human and mouse. Cistrome-GO has two working modes: solo mode for ChIP-seq peak analysis; and ensemble mode, which integrates ChIP-seq peaks with DGE data. Cistrome-GO is freely available at http://go.cistrome.org/.

scholarly journals EnhancerAtlas 2.0: an updated resource with enhancer annotation in 586 tissue/cell types across nine species

2019 ◽  
Author(s):  
Tianshun Gao ◽  
Jiang Qian
Keyword(s):  
Large Scale ◽  
Target Gene ◽  
Target Genes ◽  
Cell Types ◽  
Regulatory Elements ◽  
Tissue Cell ◽  
Normal Tissues ◽  
Genome Wide ◽  
Wide Range ◽  
User Friendly

Abstract Enhancers are distal cis-regulatory elements that activate the transcription of their target genes. They regulate a wide range of important biological functions and processes, including embryogenesis, development, and homeostasis. As more and more large-scale technologies were developed for enhancer identification, a comprehensive database is highly desirable for enhancer annotation based on various genome-wide profiling datasets across different species. Here, we present an updated database EnhancerAtlas 2.0 (http://www.enhanceratlas.org/indexv2.php), covering 586 tissue/cell types that include a large number of normal tissues, cancer cell lines, and cells at different development stages across nine species. Overall, the database contains 13 494 603 enhancers, which were obtained from 16 055 datasets using 12 high-throughput experiment methods (e.g. H3K4me1/H3K27ac, DNase-seq/ATAC-seq, P300, POLR2A, CAGE, ChIA-PET, GRO-seq, STARR-seq and MPRA). The updated version is a huge expansion of the first version, which only contains the enhancers in human cells. In addition, we predicted enhancer–target gene relationships in human, mouse and fly. Finally, the users can search enhancers and enhancer–target gene relationships through five user-friendly, interactive modules. We believe the new annotation of enhancers in EnhancerAtlas 2.0 will facilitate users to perform useful functional analysis of enhancers in various genomes.

scholarly journals Mapping the evolving landscape of super-enhancers during cell differentiation

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yan Kai ◽  
Bin E. Li ◽  
Ming Zhu ◽  
Grace Y. Li ◽  
Fei Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
Target Gene ◽  
Target Genes ◽  
De Novo ◽  
Cell Types ◽  
Functional Enrichment ◽  
Target Gene Expression ◽  
Differentiated Cells ◽  
Super Enhancer

Abstract Background Super-enhancers are clusters of enhancer elements that play critical roles in the maintenance of cell identity. Current investigations on super-enhancers are centered on the established ones in static cell types. How super-enhancers are established during cell differentiation remains obscure. Results Here, by developing an unbiased approach to systematically analyze the evolving landscape of super-enhancers during cell differentiation in multiple lineages, we discover a general trend where super-enhancers emerge through three distinct temporal patterns: conserved, temporally hierarchical, and de novo. The three types of super-enhancers differ further in association patterns in target gene expression, functional enrichment, and 3D chromatin organization, suggesting they may represent distinct structural and functional subtypes. Furthermore, we dissect the enhancer repertoire within temporally hierarchical super-enhancers, and find enhancers that emerge at early and late stages are enriched with distinct transcription factors, suggesting that the temporal order of establishment of elements within super-enhancers may be directed by underlying DNA sequence. CRISPR-mediated deletion of individual enhancers in differentiated cells shows that both the early- and late-emerged enhancers are indispensable for target gene expression, while in undifferentiated cells early enhancers are involved in the regulation of target genes. Conclusions In summary, our analysis highlights the heterogeneity of the super-enhancer population and provides new insights to enhancer functions within super-enhancers.

scholarly journals ENdb: a manually curated database of experimentally supported enhancers for human and mouse

2019 ◽  
Author(s):  
Xuefeng Bai ◽  
Shanshan Shi ◽  
Bo Ai ◽  
Yong Jiang ◽  
Yuejuan Liu ◽  
...  
Keyword(s):  
Target Genes ◽  
Regulatory Elements ◽  
Luciferase Reporter ◽  
Chromosome Conformation ◽  
Related Information ◽  
Intergenic Regions ◽  
On Chip ◽  
User Friendly ◽  
Human And Mouse

Abstract Enhancers are a class of cis-regulatory elements that can increase gene transcription by forming loops in intergenic regions, introns and exons. Enhancers, as well as their associated target genes, and transcription factors (TFs) that bind to them, are highly associated with human disease and biological processes. Although some enhancer databases have been published, most only focus on enhancers identified by high-throughput experimental techniques. Therefore, it is highly desirable to construct a comprehensive resource of manually curated enhancers and their related information based on low-throughput experimental evidences. Here, we established a comprehensive manually-curated enhancer database for human and mouse, which provides a resource for experimentally supported enhancers, and to annotate the detailed information of enhancers. The current release of ENdb documents 737 experimentally validated enhancers and their related information, including 384 target genes, 263 TFs, 110 diseases and 153 functions in human and mouse. Moreover, the enhancer-related information was supported by experimental evidences, such as RNAi, in vitro knockdown, western blotting, qRT-PCR, luciferase reporter assay, chromatin conformation capture (3C) and chromosome conformation capture-on-chip (4C) assays. ENdb provides a user-friendly interface to query, browse and visualize the detailed information of enhancers. The database is available at http://www.licpathway.net/ENdb.

scholarly journals Super-enhancers in transcriptional regulation and genome organization

2019 ◽  
Author(s):  
Xi Wang ◽  
Murray J Cairns ◽  
Jian Yan
Keyword(s):  
Gene Networks ◽  
Target Genes ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Therapeutic Interventions ◽  
Super Enhancer ◽  
Multi Stage ◽  
Sequence Elements ◽  
Cell Type Specific

Abstract Gene expression is precisely controlled in a stage and cell-type-specific manner, largely through the interaction between cis-regulatory elements and their associated trans-acting factors. Where these components aggregate in promoters and enhancers, they are able to cooperate to modulate chromatin structure and support the engagement in long-range 3D superstructures that shape the dynamics of a cell's genomic architecture. Recently, the term ‘super-enhancer’ has been introduced to describe a hyper-active regulatory domain comprising a complex array of sequence elements that work together to control the key gene networks involved in cell identity. Here, we survey the unique characteristics of super-enhancers compared to other enhancer types and summarize the recent advances in our understanding of their biological role in gene regulation. In particular, we discuss their capacity to attract the formation of phase-separated condensates, and capacity to generate three-dimensional genome structures that precisely activate their target genes. We also propose a multi-stage transition model to explain the evolutionary pressure driving the development of super-enhancers in complex organisms, and highlight the potential for involvement in tumorigenesis. Finally, we discuss more broadly the role of super-enhancers in human health disorders and related potential in therapeutic interventions.

scholarly journals Can miNRA Indicate Risk of Illness After Continuous Exposure to M. tuberculosis?

2021 ◽  
Author(s):  
Cleonardo Augusto Silva ◽  
Arthur Ribeiro-dos-Santos ◽  
Wanderson Gonçalves Gonçalves ◽  
Pablo Pinto ◽  
Rafael Pompeu Pantoja ◽  
...  
Keyword(s):  
Infectious Diseases ◽  
Expression Profile ◽  
Immune Modulation ◽  
Target Genes ◽  
Mirna Gene ◽  
Regulatory Elements ◽  
Continuous Exposure ◽  
Small Ncrnas ◽  
Gene Network Analysis ◽  
Global Expression Profile

Molecular studies regarding regulatory elements such as small ncRNAs and their mechanisms are poorly understood in infectious diseases. Tuberculosis is one of the oldest infectious diseases of humanity, and it is still a challenge to prevent and treat it. The control of the infection as well as its diagnosis are still complex, and treatments used are linked to several side effects. This study aimed to investigate miRNA’s expression profile to identify possible biomarkers for tuberculosis. We applied NGS techniques to investigate miRNA’s global expression profile from blood samples of infected patients with tuberculosis, their respective healthy physicians, and external healthy individuals as controls. Samples from 22 individuals run through a differential expression, target genes, gene set enrichment, and miRNA-gene network analysis. We observed 153 altered miRNAs, among which, only three DEmiRNAs (hsa-let-7g-5p, hsa-miR-486-3p and hsa-miR-4732-5p) were found between the investigated patients and their respective physicians. These DEmiRNAs are suggested to play an important role in granuloma regulation and their immune physiopathology. Our results propose that miRNAs may be involved in immune modulation, regulating the repertoire of genes expressed in the immune system’s cells. Our findings encourage the application of miRNAs as potential biomarkers for tuberculosis.

scholarly journals Can miRNA Indicate Risk of Illness after Continuous Exposure to M. tuberculosis?

2021 ◽  
Vol 22 (7) ◽  
pp. 3674
Author(s):  
Cleonardo Augusto Silva ◽  
Arthur Ribeiro-dos-Santos ◽  
Wanderson Gonçalves Gonçalves ◽  
Pablo Pinto ◽  
Rafael Pompeu Pantoja ◽  
...  
Keyword(s):  
Infectious Diseases ◽  
Immune Modulation ◽  
Target Genes ◽  
Expression Profiles ◽  
Mirna Gene ◽  
Regulatory Elements ◽  
Continuous Exposure ◽  
Network Analyses ◽  
Small Ncrnas ◽  
Mirna Expression Profiles

The role of regulatory elements such as small ncRNAs and their mechanisms are poorly understood in infectious diseases. Tuberculosis is one of the oldest infectious diseases of humans and it is still a challenge to prevent and treat. Control of the infection, as well as its diagnosis, are still complex and current treatments used are linked to several side effects. This study aimed to identify possible biomarkers for tuberculosis by applying NGS techniques to obtain global miRNA expression profiles from 22 blood samples of infected patients with tuberculosis (n = 9), their respective healthy physicians (n = 6) and external healthy individuals as controls (n = 7). Samples were run through a pipeline consisting of differential expression, target genes, gene set enrichment and miRNA–gene network analyses. We observed 153 altered miRNAs, among which only three DEmiRNAs (hsa-let-7g-5p, hsa-miR-486-3p and hsa-miR-4732-5p) were found between the investigated patients and their respective physicians. These DEmiRNAs are suggested to play an important role in granuloma regulation and their immune physiopathology. Our results indicate that miRNAs may be involved in immune modulation by regulating gene expression in cells of the immune system. Our findings encourage the application of miRNAs as potential biomarkers for tuberculosis.

scholarly journals Bioinformatics analysis of miRNA and mRNA expression profiles to reveal the key miRNAs and genes in osteoarthritis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Pei-yan Huang ◽  
Jun-guo Wu ◽  
Jun Gu ◽  
Tie-qi Zhang ◽  
Ling-feng Li ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Expression Profile ◽  
Target Genes ◽  
Glycogen Synthase ◽  
Expression Profiles ◽  
Mirna Gene ◽  
Functional Enrichment ◽  
Joint Disease ◽  
Expression Levels ◽  
Qrt Pcr

Abstract Background Osteoarthritis (OA) is a chronic degenerative joint disease and the most frequent type of arthritis. This study aimed to identify the key miRNAs and genes associated with OA progression. Methods The GSE105027 (microRNA [miRNA/miR] expression profile; 12 OA samples and 12 normal samples) and GSE48556 (messenger RNA [mRNA] expression profile; 106 OA samples and 33 normal samples) datasets were selected from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and miRNAs (DEMs) were analyzed using the limma and ROCR packages in R, respectively. The target genes that negatively correlated with the DEMs were predicted, followed by functional enrichment analysis and construction of the miRNA-gene and miRNA-transcription factor (TF)-gene regulatory networks. Additionally, key miRNAs and genes were screened, and their expression levels were verified by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results A total of 1696 DEGs (739 upregulated and 957 downregulated) and 108 DEMs (56 upregulated and 52 downregulated) were identified in the OA samples. Furthermore, 56 target genes that negatively correlated with the DEMs were predicted and found to be enriched in three functional terms (e.g., positive regulation of intracellular protein transport) and three pathways (e.g., human cytomegalovirus infection). In addition, three key miRNAs (miR-98-5p, miR-7-5p, and miR-182-5p) and six key genes (murine double minute 2, MDM2; glycogen synthase kinase 3-beta, GSK3B; transmembrane P24-trafficking protein 10, TMED10; DDB1 and CUL4-associated factor 12, DCAF12; caspase 3, CASP3; and ring finger protein 44, RNF44) were screened, among which the miR-7-5p → TMED10/DCAF12, miR-98-5p → CASP3/RNF44, and miR-182-5p → GSK3B pairs were observed in the regulatory network. Moreover, the expression levels of TMED10, miR-7-5p, CASP3, miR-98-5p, GSK3B, and miR-182-5p showed a negative correlation with qRT-PCR verification. Conclusion MiR-98-5p, miR-7-5p, miR-182-5p, MDM2, GSK3B, TMED10, DCAF12, CASP3, and RNF44 may play critical roles in OA progression.

FFLtool: a web server for transcription factor and miRNA feed forward loop analysis in human

2019 ◽  
Vol 36 (8) ◽  
pp. 2605-2607 ◽  
Author(s):  
Gui-Yan Xie ◽  
Mengxuan Xia ◽  
Ya-Ru Miao ◽  
Mei Luo ◽  
Qiong Zhang ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Mirna Target ◽  
Target Genes ◽  
Gene Expression Regulation ◽  
Web Server ◽  
Supplementary Information ◽  
Mechanism Study ◽  
Loop Analysis ◽  
Feed Forward ◽  
Feed Forward Loop

Abstract Summary Transcription factors (TFs) and microRNAs (miRNAs) are two kinds of important regulators for transcriptional and post-transcriptional regulations. Understanding cross-talks between the two regulators and their targets is critical to reveal complex molecular regulatory mechanisms. Here, we developed FFLtool, a web server for detecting potential feed forward loop (FFL) of TF-miRNA-target regulation in human. In FFLtool, we integrated comprehensive regulations of TF-target and miRNA-target, and developed two functional modules: (i) The ‘FFL Analysis’ module can detect potential FFLs and internal regulatory networks in a user-defined gene set. FFLtool also provides three levels of evidence to illustrate the reliability for each FFL and enrichment functions for co-target genes of the same TF and miRNA; (ii) The ‘Browse FFLs’ module displays FFLs comprised of differentially or specifically expressed TFs and miRNAs and their target genes in cancers. FFLtool is a valuable resource for investigating gene expression regulation and mechanism study in biological processes and diseases. Availability and implementation FFLtool is available on http://bioinfo.life.hust.edu.cn/FFLtool/. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Regulatory Network Analysis in Estradiol-Treated Human Endothelial Cells

2021 ◽  
Vol 22 (15) ◽  
pp. 8193
Author(s):  
Daniel Pérez-Cremades ◽  
Ana B. Paes ◽  
Xavier Vidal-Gómez ◽  
Ana Mompeón ◽  
Carlos Hermenegildo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Mirna Target ◽  
Target Genes ◽  
Functional Characterization ◽  
Human Endothelial Cells ◽  
Mrna Targets ◽  
Canonical Pathways

Background/Aims: Estrogen has been reported to have beneficial effects on vascular biology through direct actions on endothelium. Together with transcription factors, miRNAs are the major drivers of gene expression and signaling networks. The objective of this study was to identify a comprehensive regulatory network (miRNA-transcription factor-downstream genes) that controls the transcriptomic changes observed in endothelial cells exposed to estradiol. Methods: miRNA/mRNA interactions were assembled using our previous microarray data of human umbilical vein endothelial cells (HUVEC) treated with 17β-estradiol (E2) (1 nmol/L, 24 h). miRNA–mRNA pairings and their associated canonical pathways were determined using Ingenuity Pathway Analysis software. Transcription factors were identified among the miRNA-regulated genes. Transcription factor downstream target genes were predicted by consensus transcription factor binding sites in the promoter region of E2-regulated genes by using JASPAR and TRANSFAC tools in Enrichr software. Results: miRNA–target pairings were filtered by using differentially expressed miRNAs and mRNAs characterized by a regulatory relationship according to miRNA target prediction databases. The analysis identified 588 miRNA–target interactions between 102 miRNAs and 588 targets. Specifically, 63 upregulated miRNAs interacted with 295 downregulated targets, while 39 downregulated miRNAs were paired with 293 upregulated mRNA targets. Functional characterization of miRNA/mRNA association analysis highlighted hypoxia signaling, integrin, ephrin receptor signaling and regulation of actin-based motility by Rho among the canonical pathways regulated by E2 in HUVEC. Transcription factors and downstream genes analysis revealed eight networks, including those mediated by JUN and REPIN1, which are associated with cadherin binding and cell adhesion molecule binding pathways. Conclusion: This study identifies regulatory networks obtained by integrative microarray analysis and provides additional insights into the way estradiol could regulate endothelial function in human endothelial cells.

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