scholarly journals Temporal epigenomic profiling identifies AHR and GLIS1 as super-enhancer controlled regulators of mesenchymal multipotency

2017 ◽  
Author(s):  
Deborah Gérard ◽  
Florian Schmidt ◽  
Aurélien Ginolhac ◽  
Martine Schmitz ◽  
Rashi Halder ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Target Genes ◽  
Expression Profiles ◽  
Open Chromatin ◽  
Temporal Data ◽  
Time Resolved ◽  
Aryl Hydrocarbon ◽  
Super Enhancer ◽  
Novel Approach ◽  
Context Specific

ABSTRACTTemporal data on gene expression and context-specific open chromatin states can improve identification of key transcription factors (TFs) and the gene regulatory networks (GRNs) controlling cellular differentiation. However, their integration remains challenging. Here, we delineate a general approach for data-driven and unbiased identification of key TFs and dynamic GRNs, called EPIC-DREM. We generated time-series transcriptomic and epigenomic profiles during differentiation of mouse multipotent bone marrow stromal cells (MSCs) towards adipocytes and osteoblasts. Using our novel approach we constructed time-resolved GRNs for both lineages. To prioritize the identified shared regulators, we mapped dynamic super-enhancers in both lineages and associated them to target genes with correlated expression profiles. We identified aryl hydrocarbon receptor (AHR) and Glis family zinc finger 1 (GLIS1) as mesenchymal key TFs controlled by dynamic MSC-specific super-enhancers that become repressed in both lineages. AHR and GLIS1 control differentiation-induced genes and we propose they function as guardians of mesenchymal multipotency.

scholarly journals Construction of miRNA-target networks using microRNA profiles of CVB3-infected HeLa cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hai Lan Yao ◽  
Mi Liu ◽  
Wen Jun Wang ◽  
Xin Ling Wang ◽  
Juan Song ◽  
...  
Keyword(s):  
Hela Cells ◽  
Regulatory Networks ◽  
Cellular Differentiation ◽  
High Throughput Sequencing ◽  
Target Genes ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
Mirna Regulation ◽  
Cvb3 Infection ◽  
Differentially Expressed Mirnas

AbstractMicroRNAs (miRNAs) play an important role in regulating gene expression in multiple biological processes and diseases. Thus, to understand changes in miRNA during CVB3 infection, specific miRNA expression profiles were investigated at 3 h, 6 h, and 9 h postinfection in HeLa cells by small-RNA high-throughput sequencing. Biological implications of 68 differentially expressed miRNAs were analyzed through GO and KEGG pathways. Interaction networks between 34 known highly differentially expressed miRNAs and targets were constructed by mirDIP and Navigator. The predicted targets showed that FAM135A, IKZF2, PLAG1, ZNF148, PHC3, LCOR and DYRK1A, which are associated with cellular differentiation and transcriptional regulation, were recognized by 8 miRNAs or 9 miRNAs through interactional regulatory networks. Seven target genes were confirmed by RT-qPCR. The results showed that the expression of DYRK1A, FAM135A, PLAG1, ZNF148, and PHC3 were obviously inhibited at 3 h, 6 h, and 9 h postinfection. The expression of LCOR did not show a significant change, and the expression of IKZF2 increased gradually with prolonged infection time. Our findings improve the understanding of the pathogenic mechanism of CVB3 infection on cellular differentiation and development through miRNA regulation, which has implications for interventional approaches to CVB3-infection therapy. Our results also provide a new method for screening target genes of microRNA regulation in virus-infected cells.

scholarly journals Transcriptional programs define intratumoral heterogeneity of Ewing sarcoma at single cell resolution

2019 ◽  
Author(s):  
M-M Aynaud ◽  
O Mirabeau ◽  
N Gruel ◽  
S Grossetête ◽  
V Boeva ◽  
...  
Keyword(s):  
Single Cell ◽  
Ewing Sarcoma ◽  
Cell Transformation ◽  
Cell Types ◽  
Intratumoral Heterogeneity ◽  
Model Systems ◽  
Open Chromatin ◽  
Sequencing Data ◽  
Time Resolved ◽  
Super Enhancer

SummaryEWSR1-FLI1, the chimeric oncogene specific for Ewing sarcoma (EwS), induces a cascade of signaling events leading to cell transformation. However, it remains elusive how genetically homogeneous EwS cells can drive heterogeneity of transcriptional programs. Here, we combined independent component analysis of single cell RNA-sequencing data from diverse cell types and model systems with time-resolved mapping of EWSR1-FLI1 binding sites and of open chromatin regions to characterize dynamic cellular processes associated with EWSR1-FLI1 activity. We thus defined an exquisitely specific and direct, super-enhancer-driven EWSR1-FLI1 program. In EwS tumors, cell proliferation was associated with a well-defined range of EWSR1-FLI1 activity; moreover, cells with a high EWSR1-FLI1 activity presented a strong oxidative phosphorylation metabolism. In contrast, a subpopulation of cells from below and above optimal EWSR1-FLI1 activity was characterized by increased hypoxia. Overall, our study reveals sources of intratumoral heterogeneity within Ewing tumors.

scholarly journals Genome-wide identification and comparison of differentially expressed profiles of miRNAs and lncRNAs with associated ceRNA networks in the gonads of Chinese soft-shelled turtle, Pelodiscus sinensis

2019 ◽  
Author(s):  
Xiao Ma ◽  
Shuangshuang Cen ◽  
Luming Wang ◽  
Chao Zhang ◽  
Limin Wu ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Regulatory Networks ◽  
Target Genes ◽  
Expression Profiles ◽  
Integrated Analysis ◽  
Regulation Mechanism ◽  
Pelodiscus Sinensis ◽  
Specific Expression ◽  
Protein Coding ◽  
Protein Coding Genes

Abstract Abstract Background: Gonad is the major factor affecting the animal reproduction. The regulation mechanism of protein coding genes expression involved reproduction is still remains to be elucidated. Increasing evidence has shown that ncRNAs play key regulatory roles in gene expression in many life processes. The roles of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in reproduction had been investigated in some species. However, the regulation patterns of miRNA and lncRNA in sex biased expression of protein coding genes remains to be elucidated. In this study, we performed an integrated analysis of miRNA, messenger RNA (mRNA), and lncRNA expression profiles to explore their regulatory patterns in the female ovary and male testis of the soft-shelled turtle, Pelodiscus sinensis. Results: We identified 10 796 mature miRNAs, 44 678 mRNAs, and 58 923 lncRNAs in the testis and ovary. A total of 16 817 target genes were identified for miRNAs. Of these, 11 319 mRNAs, 10 495 lncRNAs, and 633 miRNAs were expressed differently. The predicted target genes of these differential expression (DE) miRNAs and lncRNAs included genes related to reproduction regulation. Furthermore, we found that 5 408 DElncRNAs and 186 DE miRNAs showed sex-specific expression. Of these, 3 miRNAs and 917 lncRNAs were testis specific and 186 DEmiRNAs and 4 491 DElncRNAs were ovary specific. We constructed compete endogenous lncRNA-miRNA-mRNA networks using bioinformatics, including 273 DEmRNAs, 5 730 DEmiRNAs, and 2 945 DElncRNAs. The target genes for the different expressed of miRNAs and lncRNAs included Wt1, Creb3l2, Gata4, Wnt2, Nr5a1, Hsd17, Igf2r, H2afz, Lin52, Trim71, Zar1, and Jazf1, etc. Conclusions: In animals, miRNA and lncRNA regulate the reproduction process, including the regulation of oocyte maturation and spermatogenesis. Considering their importance, the identified miRNAs, lncRNAs, and their targets in P. sinensis might be useful for genome editing to produce higher quality aquaculture animals. A thorough understanding of ncRNA-based cellular regulatory networks will aid in the improvement of P. sinensis reproduction traits for aquaculture.

scholarly journals Network-Based Approaches Reveal Potential Therapeutic Targets for Host-Directed Antileishmanial Therapy Driving Drug Repurposing

2021 ◽  
Author(s):  
J. Eduardo Martinez-Hernandez ◽  
Zaynab Hammoud ◽  
Alessandra Mara de Sousa ◽  
Frank Kramer ◽  
Rubens L. do Monte-Neto ◽  
...  
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Biological Process ◽  
Expression Profiles ◽  
Therapeutic Targets ◽  
Drug Repurposing ◽  
Novel Approach ◽  
Gene Regulatory ◽  
Molecular Functions ◽  
Approved Drugs

This work opens a new path to fight parasites by targeting host molecular functions by repurposing available and approved drugs. We created a novel approach to identify key proteins involved in any biological process by combining gene regulatory networks and expression profiles.

scholarly journals Comprehensive Annotation and Functional Exploration of MicroRNAs in Lettuce

2021 ◽  
Vol 12 ◽  
Author(s):  
Yang Deng ◽  
Yajuan Qin ◽  
Pan Yang ◽  
Jianjun Du ◽  
Zheng Kuang ◽  
...  
Keyword(s):  
Regulatory Network ◽  
Regulatory Networks ◽  
Target Genes ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Computational Prediction ◽  
Regulatory Relationship ◽  
Specific Expression ◽  
Economic Significance ◽  
Specific Expression Pattern

MicroRNA (miRNA) is an important endogenous post-transcriptional regulator, while lettuce (Lactuca sativa) is a leafy vegetable of global economic significance. However, there are few studies on miRNAs in lettuce, and research on miRNA regulatory network in lettuce is absent. In this study, through deep sequencing of small RNAs in different tissues, together with a reference genome, 157 high-confidence miRNA loci in lettuce were comprehensively identified, and their expression patterns were determined. Using a combination of computational prediction and high-throughput experimental verification, a set of reliable lettuce miRNA targets were obtained. Furthermore, through RNA-Seq, the expression profiles of these targets and a comprehensive view of the negative regulatory relationship between miRNAs and their targets was acquired based on a correlation analysis. To further understand miRNA functions, a miRNA regulatory network was constructed, with miRNAs at the core and combining transcription factors and miRNA target genes. This regulatory network, mainly composed of feed forward loop motifs, greatly increases understanding of the potential functions of miRNAs, and many unknown potential regulatory links were discovered. Finally, considering its specific expression pattern, Lsa-MIR408 as a hub gene was employed to illustrate the function of the regulatory network, and genetic experiments revealed its ability to increase the fresh weight and achene size of lettuce. In short, this work lays a solid foundation for the study of miRNA functions and regulatory networks in lettuce.

scholarly journals Chromatin accessibility variations across pancreatic islet maturation

2019 ◽  
Author(s):  
Jonathan Sobel ◽  
Claudiane Guay ◽  
Adriana Rodriguez-Trejo ◽  
Lisa Stoll ◽  
Véronique Menoud ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Islet ◽  
Regulatory Networks ◽  
Neonatal Period ◽  
Expression Profiles ◽  
Cell Mass ◽  
Chromatin Accessibility ◽  
Cellular Reprogramming ◽  
Open Chromatin ◽  
Adult Rat

Glucose-induced insulin secretion, a peculiar property of fully mature β-cells, is only achieved after birth and is preceded by a phase of intense proliferation. These events occurring in the neonatal period are decisive for the establishment of an appropriate functional β-cell mass that provides the required insulin throughout life. However, key regulators of gene expression involved in cellular reprogramming along pancreatic islet maturation remain to be elucidated. The present study addressed this issue by mapping open chromatin regions in newborn versus adult rat islets using the ATAC-seq assay. Accessible regions were then correlated with the expression profiles of mRNAs to unveil the regulatory networks governing functional islet maturation. This led to the identification of Scrt1, a novel transcriptional repressor controlling β-cell proliferation.

scholarly journals SOX transcription factors direct TCF-independent WNT/beta-catenin transcription.

2021 ◽  
Author(s):  
Shreyasi Mukherjee ◽  
David M Luedeke ◽  
Leslie Brown ◽  
Aaron Zorn
Keyword(s):  
Transcription Factors ◽  
Tissue Regeneration ◽  
Pluripotent Stem Cells ◽  
Target Genes ◽  
Fundamental Question ◽  
Beta Catenin ◽  
Cell Type ◽  
Time Resolved ◽  
Specific Manner ◽  
Context Specific

WNT/β-catenin signaling regulates gene expression across numerous biological contexts including development, stem cell homeostasis and tissue regeneration, and dysregulation of this pathway has been implicated in many diseases including cancer. One fundamental question is how distinct WNT target genes are activated in a context-specific manner, given the dogma that most, if not all, WNT/β-catenin responsive transcription is mediated by TCF/LEF transcription factors (TFs) that have similar DNA-binding specificities. Here we show that the SOX family of TFs direct lineage-specific WNT/β-catenin responsive transcription during the differentiation of human pluripotent stem cells (hPSCs) into definitive endoderm (DE) and neuromesodermal progenitors (NMPs). Using time-resolved multi-omics analyses, we show that β-catenin association with chromatin is highly dynamic, colocalizing with distinct TCFs and/or SOX TFs at distinct stages of differentiation, indicating both cooperative and competitive modes of genomic interactions. We demonstrate that SOX17 and SOX2 are required to recruit β-catenin to hundreds of lineage-specific WNT-responsive enhancers, many of which are not occupied by TCFs. At a subset of these TCF-independent enhancers, SOX TFs are required to both establish a permissive chromatin landscape and recruit a WNT-enhanceosome complex that includes β-catenin, BCL9, PYGO and transcriptional coactivators to direct SOX/β-catenin-dependent transcription. Given that SOX TFs are expressed in almost every cell type, these results have broad mechanistic implications for the specificity of WNT responses across many developmental and disease contexts.

scholarly journals UniPath: A uniform approach for pathway and gene-set based analysis of heterogeneity in single-cell epigenome and transcriptome profiles

2019 ◽  
Author(s):  
Smriti Chawla ◽  
Sudhagar Samydurai ◽  
Say Li Kong ◽  
Zhenxun Wang ◽  
Wai Leong Tam ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Single Cells ◽  
Gene Expression Profiles ◽  
Cell Types ◽  
Mouse Cell ◽  
Open Chromatin ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Specific Regulation ◽  
Context Specific

AbstractHere, we introduce UniPath, for representing single-cells using pathway and gene-set enrichment scores by a transformation of their open-chromatin or gene-expression profiles. Besides being robust to variability in dropout, UniPath provides consistency and scalability in estimating gene-set enrichment scores for every cell. UniPath’s approach of predicting temporal-order of single-cells using their gene-set activity score enables suppression of known covariates. UniPath based analysis of mouse cell atlas yielded surprising, albeit biologically-meaningful co-clustering of cell-types from distant organs and helped in annotating many unlabeled cells. By enabling unconventional analysis, UniPath also proves to be useful in inferring context-specific regulation in cancer cells.

scholarly journals Human genetic variants associated with COVID-19 severity are enriched in immune and epithelium regulatory networks

2021 ◽  
Author(s):  
Zhanying Feng ◽  
Xianwen Ren ◽  
Zhana Duren ◽  
Yong Wang
Keyword(s):  
Immune Cells ◽  
Genetic Variants ◽  
Chemokine Receptors ◽  
Regulatory Networks ◽  
Target Genes ◽  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Context Specific ◽  
Epithelium Cells

Human genetic variants can influence the severity of infection with SARS-COV-2. Several genome-wide association studies (GWAS) have been conducted to identify human risk loci that may be involved with COVID-19 severity. However, candidate genes were investigated in the genomic proximity of each locus without considering their functional cellular contexts. Here, we compiled regulatory networks of 77 human contexts to interpret these risk loci by revealing their relevant contexts and associated transcript factors (TF), regulatory elements (REs), and target genes (TGs). 21 human contexts were identified to be associated with COVID-19 severity and grouped into two categories: immune cells and epithelium cells. We further investigated the risk loci in regulatory network of immune cells, epithelium cells and their crosstalk. Two genomic clusters, chemokine receptors cluster and OAS cluster showed the strongest association with COVID-19 severity in the context specific regulatory networks.

scholarly journals microRNA–mRNA regulatory networks underlying chronic mucus hypersecretion in COPD

2018 ◽  
Vol 52 (3) ◽  
pp. 1701556 ◽  
Author(s):  
Hataitip Tasena ◽  
Alen Faiz ◽  
Wim Timens ◽  
Jacobien Noordhoek ◽  
Machteld N. Hylkema ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Target Genes ◽  
Expression Profiles ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Mucus Hypersecretion ◽  
Mrna Targets ◽  
Copd Patients

Chronic mucus hypersecretion (CMH) is a common feature in chronic obstructive pulmonary disease (COPD) and is associated with worse prognosis and quality of life. This study aimed to identify microRNA (miRNA)–mRNA regulatory networks underlying CMH.The expression profiles of miRNA and mRNA in bronchial biopsies from 63 COPD patients were associated with CMH using linear regression. Potential mRNA targets of each CMH-associated miRNA were identified using Pearson correlations. Gene set enrichment analysis (GSEA) and STRING (search tool for the retrieval of interacting genes/proteins) analysis were used to identify key genes and pathways.20 miRNAs and 539 mRNAs were differentially expressed with CMH in COPD. The expression of 10 miRNAs was significantly correlated with the expression of one or more mRNAs. Of these, miR-134-5p, miR-146a-5p and the let-7 family had the highest representation of CMH-associated mRNAs among their negatively correlated predicted targets. KRAS and EDN1 were identified as key regulators of CMH and were negatively correlated predicted targets of miR-134-5p and let-7a-5p, let-7d-5p, and let-7f-5p, respectively. GSEA suggested involvement of MUC5AC-related genes and several other relevant gene sets in CMH. The lower expression of miR-134-5p was confirmed in primary airway fibroblasts from COPD patients with CMH.We identified miR-134-5p, miR-146a-5p and let-7 family, along with their potential target genes including KRAS and EDN1, as potential key miRNA–mRNA networks regulating CMH in COPD.

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