Evolution of miRNA binding sites and regulatory networks in cichlids

2021 ◽  
Author(s):  
Tarang K Mehta ◽  
Luca Penso-Dolfin ◽  
Will K Nash ◽  
Sushmita Roy ◽  
Federica Di Palma ◽  
...  
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Regulatory Networks ◽  
Target Genes ◽  
Phenotypic Diversity ◽  
Regulatory Regions ◽  
Adaptive Trait ◽  
Regulatory Variants ◽  
Key Driver ◽  
Species Specific

The divergence of regulatory regions and gene regulatory network (GRN) rewiring is a key driver of cichlid phenotypic diversity. However, the contribution of miRNA binding site turnover has yet to be linked to GRN evolution across cichlids. Here, we extend our previous studies by analysing the selective constraints driving evolution of miRNA and transcription factor (TF) binding sites of target genes, to infer instances of cichlid GRN rewiring associated with regulatory binding site turnover. Comparative analyses identified increased species-specific networks that are functionally associated to traits of cichlid phenotypic diversity. The evolutionary rewiring is associated with differential models of miRNA snd TF binding site turnover, driven by a high proportion of fast-evolving polymorphic sites in adaptive trait genes compared to subsets of random genes. Positive selection acting upon discrete mutations in these regulatory regions is likely to be an important mechanism in rewiring GRNs in rapidly radiating cichlids. Regulatory variants of functionally associated miRNA and TF binding sites of visual opsin genes differentially segregate according to phylogeny and ecology of Lake Malawi species, identifying both rewired e.g. clade-specific and conserved network motifs of adaptive trait associated GRNs. Our approach revealed several novel candidate regulators, regulatory regions and three-node motifs across cichlid genomes with previously reported associations to known adaptive evolutionary traits.

scholarly journals Common binding by redundant group B Sox proteins is evolutionarily conserved in Drosophila

2014 ◽  
Author(s):  
Sarah H Carl ◽  
Steven Russell
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Regulatory Networks ◽  
System Development ◽  
Nervous System Development ◽  
Phylogenetic Distance ◽  
Functional Sites ◽  
Sox Proteins ◽  
Alternative Sources ◽  
Group B

Background: Group B Sox proteins are a highly conserved group of transcription factors that act extensively to coordinate nervous system development in higher metazoans while showing both co-expression and functional redundancy across a broad group of taxa. In Drosophila melanogaster, the two group B Sox proteins Dichaete and SoxNeuro show widespread common binding across the genome. While some instances of functional compensation have been observed in Drosophila, the function of common binding and the extent of its evolutionary conservation is not known. Results: We used DamID-seq to examine the genome-wide binding patterns of Dichaete and SoxNeuro in four species of Drosophila. Through a quantitative comparison of Dichaete binding, we evaluated the rate of binding site turnover across the genome as well as at specific functional sites. We also examined the presence of Sox motifs within binding intervals and the correlation between sequence conservation and binding conservation. To determine whether common binding between Dichaete and SoxNeuro is conserved, we performed a detailed analysis of the binding patterns of both factors in two species. Conclusion: We find that, while the regulatory networks driven by Dichaete and SoxNeuro are largely conserved across the drosophilids studied, binding site turnover is widespread and correlated with phylogenetic distance. Nonetheless, binding is preferentially conserved at known cis-regulatory modules and core, independently verified binding sites. We observed the strongest binding conservation at sites that are commonly bound by Dichaete and SoxNeuro, suggesting that these sites are functionally important. Our analysis provides insights into the evolution of group B Sox function, highlighting the specific conservation of shared binding sites and suggesting alternative sources of neofunctionalisation between paralogous family members.

scholarly journals The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2690
Author(s):  
Mónica Fernández-Cortés ◽  
Eduardo Andrés-León ◽  
Francisco Javier Oliver
Keyword(s):  
Transcription Factors ◽  
Binding Sites ◽  
Regulatory Networks ◽  
Target Genes ◽  
Parp Inhibitor ◽  
Vasculogenic Mimicry ◽  
Transcriptome Profiling ◽  
Key Species ◽  
Non Coding Rnas ◽  
The Impact

In highly metastatic tumors, vasculogenic mimicry (VM) involves the acquisition by tumor cells of endothelial-like traits. Poly-(ADP-ribose) polymerase (PARP) inhibitors are currently used against tumors displaying BRCA1/2-dependent deficient homologous recombination, and they may have antimetastatic activity. Long non-coding RNAs (lncRNAs) are emerging as key species-specific regulators of cellular and disease processes. To evaluate the impact of olaparib treatment in the context of non-coding RNA, we have analyzed the expression of lncRNA after performing unbiased whole-transcriptome profiling of human uveal melanoma cells cultured to form VM. RNAseq revealed that the non-coding transcriptomic landscape differed between olaparib-treated and non-treated cells: olaparib significantly modulated the expression of 20 lncRNAs, 11 lncRNAs being upregulated, and 9 downregulated. We subjected the data to different bioinformatics tools and analysis in public databases. We found that copy-number variation alterations in some olaparib-modulated lncRNAs had a statistically significant correlation with alterations in some key tumor suppressor genes. Furthermore, the lncRNAs that were modulated by olaparib appeared to be regulated by common transcription factors: ETS1 had high-score binding sites in the promoters of all olaparib upregulated lncRNAs, while MZF1, RHOXF1 and NR2C2 had high-score binding sites in the promoters of all olaparib downregulated lncRNAs. Finally, we predicted that olaparib-modulated lncRNAs could further regulate several transcription factors and their subsequent target genes in melanoma, suggesting that olaparib may trigger a major shift in gene expression mediated by the regulation lncRNA. Globally, olaparib changed the lncRNA expression landscape during VM affecting angiogenesis-related genes.

scholarly journals Genome-Wide microRNA Profiling Using Oligonucleotide Microarray Reveals Regulatory Networks of microRNAs in Nicotiana benthamiana During Beet Necrotic Yellow Vein Virus Infection

Viruses ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 310 ◽  
Author(s):  
Junying Liu ◽  
Huiyan Fan ◽  
Ying Wang ◽  
Chenggui Han ◽  
Xianbing Wang ◽  
...  
Keyword(s):  
Nicotiana Benthamiana ◽  
Regulatory Networks ◽  
Target Genes ◽  
Tobacco Rattle Virus ◽  
Yellow Vein ◽  
Differentially Expressed ◽  
Virus Induced Gene Silencing ◽  
Developmental Defects ◽  
Differentially Expressed Mirnas ◽  
Species Specific

Beet necrotic yellow vein virus (BNYVV) infections induce stunting and leaf curling, as well as root and floral developmental defects and leaf senescence in Nicotiana benthamiana. A microarray analysis with probes capable of detecting 1596 candidate microRNAs (miRNAs) was conducted to investigate differentially expressed miRNAs and their targets upon BNYVV infection of N. benthamiana plants. Eight species-specific miRNAs of N. benthamiana were identified. Comprehensive characterization of the N. benthamiana microRNA profile in response to the BNYVV infection revealed that 129 miRNAs were altered, including four species-specific miRNAs. The targets of the differentially expressed miRNAs were predicted accordingly. The expressions of miR164, 160, and 393 were up-regulated by BNYVV infection, and those of their target genes, NAC21/22, ARF17/18, and TIR, were down-regulated. GRF1, which is a target of miR396, was also down-regulated. Further genetic analysis of GRF1, by Tobacco rattle virus-induced gene silencing, assay confirmed the involvement of GRF1 in the symptom development during BNYVV infection. BNYVV infection also induced the up-regulation of miR168 and miR398. The miR398 was predicted to target umecyanin, and silencing of umecyanin could enhance plant resistance against viruses, suggesting the activation of primary defense response to BNYVV infection in N. benthamiana. These results provide a global profile of miRNA changes induced by BNYVV infection and enhance our understanding of the mechanisms underlying BNYVV pathogenesis.

scholarly journals Powerful Induction of Divergent tgs1-Rv3131 Genes in Mycobacterium tuberculosis Is Mediated by DevR Interaction with a High-Affinity Site and an Adjacent Cryptic Low-Affinity Site

2009 ◽  
Vol 191 (19) ◽  
pp. 6075-6081 ◽  
Author(s):  
Santosh Chauhan ◽  
Jaya Sivaswami Tyagi
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Binding Site ◽  
Binding Sites ◽  
Target Genes ◽  
Promoter Activation ◽  
Transcription Start ◽  
High Affinity ◽  
Synergistic Activation ◽  
Dnase I Footprinting ◽  
High Affinity Site

ABSTRACT DevR activates the transcription of ∼48 genes in response to hypoxia and other stresses and triggers metabolic downshift and dormancy development in Mycobacterium tuberculosis. tgs1 and Rv3131 encode triacylglycerol synthase and a putative nitroreductase, respectively, and both are members of the DevR regulon. This study aimed to understand how a single putative DevR binding site identified previously could sustain powerful induction of divergent tgs1-Rv3131 genes. DNase I footprinting revealed that phosphorylated DevR in fact binds to two sites symmetrically located at −42.5 and −63.5 bp from transcription start points of both genes. DevR first bound to the high-affinity site, P, and cooperatively recruited another DevR molecule to the secondary low-affinity site, S, to activate tgs1-Rv3131 transcription by ∼210- and ∼110-fold, respectively. The presence of a single P site significantly reduced activation of tgs1 expression and abolished Rv3131 activity, reinforcing the requirement of two binding sites for robust expression in both directions. P site inversion abolished tgs1 but not Rv3131 transcription despite DevR occupancy at both sites. The lack of tgs1 expression is most likely due to disruption of its −35 promoter element rather than inversion of the binding site per se. We conclude that (i) an overlap of a DevR binding site and −35 sequence is indispensable for promoter activation, (ii) DevR interaction with two binding sites is obligatory for synergistic activation of tgs1-Rv3131 promoters, and (iii) DevR interaction with binding sites of different affinities offers scope for temporal and differential expression of target genes.

scholarly journals Probing transcription factor combinatorics in different promoter classes and in enhancers

2017 ◽  
Author(s):  
Jimmy Vandel ◽  
Océane Cassan ◽  
Sophie Lèbre ◽  
Charles-Henri Lecellier ◽  
Laurent Bréhélin
Keyword(s):  
Binding Sites ◽  
Target Genes ◽  
Cell Types ◽  
Model Parameters ◽  
Binding Motif ◽  
Cell Type ◽  
Regulatory Regions ◽  
New Approach ◽  
Cell Type Specific ◽  
Common Target

In eukaryotic cells, transcription factors (TFs) are thought to act in a combinatorial way, by competing and collaborating to regulate common target genes. However, several questions remain regarding the conservation of these combina-tions among different gene classes, regulatory regions and cell types. We propose a new approach named TFcoop to infer the TF combinations involved in the binding of a tar-get TF in a particular cell type. TFcoop aims to predict the binding sites of the target TF upon the binding affinity of all identified cooperating TFs. The set of cooperating TFs and model parameters are learned from ChIP-seq data of the target TF. We used TFcoop to investigate the TF combina-tions involved in the binding of 106 TFs on 41 cell types and in four regulatory regions: promoters of mRNAs, lncRNAs and pri-miRNAs, and enhancers. We first assess that TFcoop is accurate and outperforms simple PWM methods for pre-dicting TF binding sites. Next, analysis of the learned models sheds light on important properties of TF combinations in different promoter classes and in enhancers. First, we show that combinations governing TF binding on enhancers are more cell-type specific than that governing binding in pro-moters. Second, for a given TF and cell type, we observe that TF combinations are different between promoters and en-hancers, but similar for promoters of mRNAs, lncRNAs and pri-miRNAs. Analysis of the TFs cooperating with the dif-ferent targets show over-representation of pioneer TFs and a clear preference for TFs with binding motif composition similar to that of the target. Lastly, our models accurately dis-tinguish promoters associated with specific biological processes.

C/EBPε Plays a Role in Immunity By Regulating Trem-1 Expression in Granulocytes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4100-4100
Author(s):  
Hyung Chan Suh ◽  
Tong Yin ◽  
Touati Benoukraf ◽  
Jonathan Said ◽  
Stephen Lee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Inflammatory Response ◽  
Binding Site ◽  
Binding Sites ◽  
Target Genes ◽  
Bone Marrow Cells ◽  
Luciferase Assay ◽  
Wild Type ◽  
Granulocytic Differentiation ◽  
Marrow Cells

Abstract C/EBPepsilon (C/EBPε) knock-out (KO) mice have defects in granulocytic development and increased susceptibility to infection. We also observed a unique phenotype of C/EBPε KO mice showing prolonged lower grade, mild skin problems such as hair loss that progressed to severe wound problems; abdominal wall perforation to the peritoneum as well as mandibular skin perforation to the oral cavity, without significant clinical symptoms. The observation suggests inappropriate response to inflammation by loss of C/EBPε. To understand the functional defects of these granulocytes, we performed a systematic approach with ChIP-seq and microarray of bone marrow cells from C/EBPε KO mice. Duplicate ChIP-seq libraries were prepared from bone marrow cells of wild type and C/EBPε KO mice using two different C/EBPε specific antibodies. Analysis of pooled data identified 14,253 C/EBPε binding sites, and 12,865 of these binding sites overlapped with the two antibodies. Sixteen percent of C/EBPε binding sites were in the promoter regions within 1 kb of the transcriptional start sites. Direct canonical C/EBPε target genes were defined by 1.5 log2 fold or greater increase in expression in the Gr-1+/Mac-1+ cells of wild type bone marrow cells compared to those of the KO mice. 2,224 genes met this criteria including previously identified target genes, such as ltf, camp, ngp, of which 988 genes were bound by C/EBPε. C/EBPε bound to the promoter sites of 150 genes and the enhancer region of 838 genes. The other 1,236 up-regulated genes did not have binding of C/EBPε, suggesting their up-regulation was a secondary event during terminal granulocytic differentiation. Electromobility shift assay followed by antibody supershift confirmed that C/EBPε was able to bind to upstream regions of target genes such as lft, ngp, il-1b. Trem-1 is an amplifier of inflammatory response. Increased expression/activation of Trem-1 on neutrophil membranes takes part in cytokine production, phagocytosis, apoptosis, oxidative burst by cooperating with TLR4 in response to environmental conditions. Soluble TREM1 levels increase even in neutopenic patients, suggesting it is associated with emergent granulopoiesis in response to infection or inflammation. The expression of Trem-1 is regulated by NF-kB and PU.1. Trem-1 KO mice have reduced inflammation without defects in clearance of pathogens in mice. Considering previous reports demonstrating TLR4 increases transcription of C/EBP and potentiates transcriptional activity of C/EBP via NF-kB, regulatory loops between TLR4/NF-kB/C/EBP/Trem-1 may exist and regulate inflammatory response. ChIP-seq illustrated a C/EBPε binding site located 92 bp upstream from transcription start site of Trem-1 (GTTGTGAAAC). Microarray comparison of Trem-1 expression in Gr-1+/Mac-1+ bone marrow cells showed 5.3 log2 fold decreased gene expression in C/EBPε KO versus wild type mice. To confirm microarray data, quantitative PCR were performed with sorted Gr-1+ bone marrow cells from wild type and KO mice. The qPCR demonstrated that trem-1 expression of C/EBPε KO cells was 60% of wild type (p=0.001). A pGL3 basic luciferase vector with the first 291bp upstream of trem-1containing a putative C/EBPε binding site was cloned and co-transfected with 2 ug of C/EBPε expressing vector into 293T cells. The dual luciferase assay, normalized by renilla luciferase, showed 8 fold increase by C/EBPε (p<0.0001). In conclusion, we identified trem-1 as a downstream target of C/EBPε, which completes a positive regulatory loop of TLR4-NF-kB-C/EBPε-Trem1-TLR4 in response to inflammatory signal. Therefore, C/EBPε KO mice have an inappropriate inflammatory response by loss of the positive amplificatory loop, in addition to previously known defective clearance of pathogen by their inability to produce secondary granules. Disclosures No relevant conflicts of interest to declare.

scholarly journals Comparison of reprogramming factor targets reveals both species-specific and conserved mechanisms in early iPS cells

2017 ◽  
Author(s):  
Kai Fu ◽  
Constantinos Chronis ◽  
Abdenour Soufi ◽  
Giancarlo Bonora ◽  
Miguel Edwards ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Target Genes ◽  
Human Fibroblasts ◽  
Mouse Cell ◽  
Binding Motifs ◽  
Reprogramming Factors ◽  
Early Mouse ◽  
Species Specific ◽  
Human And Mouse ◽  
Syntenic Regions

AbstractBoth human and mouse fibroblasts can be reprogrammed to pluripotency with Oct4, Sox2, Klf4, and c-Myc (OSKM) transcription factors. While both systems generate pluripotency, human reprogramming takes considerably longer than mouse. To assess additional similarities and differences, we sought to compare the binding of the reprogramming factors between the two systems. In human fibroblasts, the OSK factors initially target many more closed chromatin sites compared to mouse. Despite this difference, the intra- and intergenic distribution of target sites, target genes, primary binding motifs, and combinatorial binding patterns between the reprogramming factors are largely shared. However, while many OSKM binding events in early mouse cell reprogramming occur in syntenic regions, only a limited number is conserved in human. In summary, these findings suggest similar general effects of OSKM binding across these two species, even though the detailed regulatory networks have diverged significantly.

scholarly journals The N.C.Yeastract and CommunityYeastract databases to study gene and genomic transcription regulation in non-conventional yeasts

2021 ◽  
Vol 21 (6) ◽  
Author(s):  
Cláudia P Godinho ◽  
Margarida Palma ◽  
Jorge Oliveira ◽  
Marta N Mota ◽  
Miguel Antunes ◽  
...  
Keyword(s):  
Binding Sites ◽  
Regulatory Networks ◽  
Target Genes ◽  
Kluyveromyces Lactis ◽  
Weak Acid ◽  
Zygosaccharomyces Bailii ◽  
Spoilage Yeast ◽  
Yeast Community ◽  
Acid Tolerant ◽  
Yeast Yarrowia Lipolytica

ABSTRACT Responding to the recent interest of the yeast research community in non-Saccharomyces cerevisiae species of biotechnological relevance, the N.C.Yeastract (http://yeastract-plus.org/ncyeastract/) was associated to YEASTRACT + (http://yeastract-plus.org/). The YEASTRACT + portal is a curated repository of known regulatory associations between transcription factors (TFs) and target genes in yeasts. N.C.Yeastract gathers all published regulatory associations and TF-binding sites for Komagataellaphaffii (formerly Pichia pastoris), the oleaginous yeast Yarrowia lipolytica, the lactose fermenting species Kluyveromyces lactis and Kluyveromyces marxianus, and the remarkably weak acid-tolerant food spoilage yeast Zygosaccharomyces bailii. The objective of this review paper is to advertise the update of the existing information since the release of N.C.Yeastract in 2019, and to raise awareness in the community about its potential to help the day-to-day work on these species, exploring all the information available in the global YEASTRACT + portal. Using simple and widely used examples, a guided exploitation is offered for several tools: (i) inference of orthologous genes; (ii) search for putative TF binding sites and (iii) inter-species comparison of transcription regulatory networks and prediction of TF-regulated networks based on documented regulatory associations available in YEASTRACT + for well-studied species. The usage potentialities of the new CommunityYeastract platform by the yeast community are also discussed.

scholarly journals Transcriptional regulation of a mouse Clara cell-specific protein (mCC10) gene by the NKx transcription factor family members thyroid transciption factor 1 and cardiac muscle-specific homeobox protein (CSX).

1996 ◽  
Vol 16 (5) ◽  
pp. 2056-2064 ◽  
Author(s):  
M K Ray ◽  
C Y Chen ◽  
R J Schwartz ◽  
F J DeMayo
Keyword(s):  
Transcription Factor ◽  
Cardiac Muscle ◽  
Binding Site ◽  
Binding Sites ◽  
Promoter Region ◽  
Target Genes ◽  
Clara Cell ◽  
Proximal Promoter ◽  
Growth Hormone Gene ◽  
Homeobox Protein

This report defines the elements between bp -800 and -166 that regulate the quantitative level of mouse CC10 (mCC10) transcription in the lungs. The elements in this promoter domain are the response elements for the NKx2.1 homeobox protein, thyroid transcription factor 1 (TTF1). DNase I footprint analysis identified five binding sites for TTF1 between bp -800 and - 166. These sites are located at bp -344 to -335, - 282 to -273, -268 to -263, -258 to -249, and - 199 to - 190. In addition to these enhancer elements, two TTF1 binding sites were identified in the proximal promoter region (bp - 166 to + 1), at bp -74 to -69 and -49 to -39. An identical footprint of the mCC10 promoter region was also observed with another member of the NKx family, NKx 2.5, the cardiac muscle-specific homeobox protein (CSX). Deletion and linker-scanner mutational analyses of the TTF1 binding sites in the mCC10 distal promoter region with transient cotransfection into CV1 cells with either TTF1 or CSX identified the site located between bp -282 and -273 as the major regulator of CC10 expression, with minor regulation by sites at bp -344 to -335 and -258 to -249. The importance of the NKx binding site at bp -282 to -273 was verified in vivo. Transgenic mice generated with the human growth hormone gene fused to 800 bp of the mCC10 promoter containing a mutation in the TTF1 binding site at bp -282 to -273 showed a reduction in transgene expression equal to that of the mice generated with only 166 bp of 5'-flanking DNA. This report emphasizes the importance of TTF1 or related factors as major regulators of pulmonary gene expression and demonstrates the potential of NKx proteins to bind and activate heterologous target genes.

Sign in / Sign up

Export Citation Format

Share Document