scholarly journals The Role of Chromatin Accessibility in cis-Regulatory Evolution

2019 ◽  
Vol 11 (7) ◽  
pp. 1813-1828 ◽  
Author(s):  
Pei-Chen Peng ◽  
Pierre Khoueiry ◽  
Charles Girardot ◽  
James P Reddington ◽  
David A Garfield ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Developmental Stages ◽  
Chromatin Accessibility ◽  
Drosophila Virilis ◽  
Binding Motif ◽  
Evolutionary Divergence ◽  
Core Network ◽  
Enhancer Activity ◽  
Mesoderm Specification

Abstract Transcription factor (TF) binding is determined by sequence as well as chromatin accessibility. Although the role of accessibility in shaping TF-binding landscapes is well recorded, its role in evolutionary divergence of TF binding, which in turn can alter cis-regulatory activities, is not well understood. In this work, we studied the evolution of genome-wide binding landscapes of five major TFs in the core network of mesoderm specification, between Drosophila melanogaster and Drosophila virilis, and examined its relationship to accessibility and sequence-level changes. We generated chromatin accessibility data from three important stages of embryogenesis in both Drosophila melanogaster and Drosophila virilis and recorded conservation and divergence patterns. We then used multivariable models to correlate accessibility and sequence changes to TF-binding divergence. We found that accessibility changes can in some cases, for example, for the master regulator Twist and for earlier developmental stages, more accurately predict binding change than is possible using TF-binding motif changes between orthologous enhancers. Accessibility changes also explain a significant portion of the codivergence of TF pairs. We noted that accessibility and motif changes offer complementary views of the evolution of TF binding and developed a combined model that captures the evolutionary data much more accurately than either view alone. Finally, we trained machine learning models to predict enhancer activity from TF binding and used these functional models to argue that motif and accessibility-based predictors of TF-binding change can substitute for experimentally measured binding change, for the purpose of predicting evolutionary changes in enhancer activity.

scholarly journals The role of chromatin accessibility in cis-regulatory evolution

2018 ◽  
Author(s):  
Pei-Chen Peng ◽  
Pierre Khoueiry ◽  
Charles Girardot ◽  
James P. Reddington ◽  
David A. Garfield ◽  
...  
Keyword(s):  
Developmental Stages ◽  
Chromatin Accessibility ◽  
Binding Motif ◽  
Evolutionary Divergence ◽  
Core Network ◽  
Enhancer Activity ◽  
Mesoderm Specification ◽  
Evolutionary Changes ◽  
In Cis

ABSTRACTTranscription factor (TF) binding is determined by sequence as well as chromatin accessibility. While the role of accessibility in shaping TF-binding landscapes is well recorded, its role in evolutionary divergence of TF binding, which in turn can alter cis-regulatory activities, is not well understood. In this work, we studied the evolution of genome-wide binding landscapes of five major transcription factors (TFs) in the core network of mesoderm specification, between D. melanogaster and D. virilis, and examined its relationship to accessibility and sequence-level changes. We generated chromatin accessibility data from three important stages of embryogenesis in both D. melanogaster and D. virilis, and recorded conservation and divergence patterns. We then used multi-variable models to correlate accessibility and sequence changes to TF binding divergence. We found that accessibility changes can in some cases, e.g., for the master regulator Twist and for earlier developmental stages, more accurately predict binding change than is possible using TF binding motif changes between orthologous enhancers. Accessibility changes also explain a significant portion of the co-divergence of TF pairs. We noted that accessibility and motif changes offer complementary views of the evolution of TF binding, and developed a combined model that captures the evolutionary data much more accurately than either view alone. Finally, we trained machine learning models to predict enhancer activity from TF binding, and used these functional models to argue that motif and accessibility-based predictors of TF binding change can substitute for experimentally measured binding change, for the purpose of predicting evolutionary changes in enhancer activity.

scholarly journals Zscan4c activates endogenous retrovirus MERVL and cleavage embryo genes

2019 ◽  
Author(s):  
Weiyu Zhang ◽  
Fuquan Chen ◽  
Ruiqing Chen ◽  
Dan Xie ◽  
Jiao Yang ◽  
...  
Keyword(s):  
Developmental Stages ◽  
Embryonic Stem ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Enhancer Activity ◽  
Cell Cleavage ◽  
Cell Embryo ◽  
And Function ◽  
Scan Domain

AbstractEndogenous retroviruses (ERVs) contribute to ∼10 percent of the mouse genome. They are often silenced in differentiated somatic cells but differentially expressed at various embryonic developmental stages. A minority of mouse embryonic stem cells (ESCs), like 2-cell cleavage embryos, highly express ERV MERVL. However, the role of ERVs and mechanism of their activation in these cells are still poorly understood. In this study, we investigated the regulation and function of the stage-specific expressed ERVs, with a particular focus on the totipotency marker MT2/MERVL. We show that the transcription factor Zscan4c functions as an activator of MT2/MERVL and 2-cell/4-cell embryo genes. Zinc finger domains of Zscan4c play an important role in this process. In addition, Zscan4c interacts with MT2 and regulates MT2-nearby 2-cell/4-cell genes through promoting enhancer activity of MT2. Furthermore, MT2 activation is accompanied by enhanced H3K4me1, H3K27ac, and H3K14ac deposition on MT2. Zscan4c also interacts with GBAF chromatin remodelling complex through SCAN domain to further activate MT2 enhancer activity. Taken together, we delineate a previously unrecognized regulatory axis that Zscan4c interacts with and activates MT2/MERVL loci and their nearby genes through epigenetic regulation.

scholarly journals Lack of the canonical pRB-binding domain in the E7 ORF of artiodactyl papillomaviruses is associated with the development of fibropapillomas

2004 ◽  
Vol 85 (5) ◽  
pp. 1243-1250 ◽  
Author(s):  
Apurva Narechania ◽  
Masanori Terai ◽  
Zigui Chen ◽  
Rob DeSalle ◽  
Robert D. Burk
Keyword(s):  
Rangifer Tarandus ◽  
Binding Domain ◽  
Binding Motif ◽  
Evolutionary Divergence ◽  
Bovine Papillomavirus ◽  
Complete Genomes ◽  
E7 Proteins ◽  
Type 3 ◽  
Complicated Mechanism

The L-X-C-X-E pRB-binding motif of papillomavirus (PV) E7 proteins has been implicated in the immortalization and transformation of the host cell. However, sequencing of the complete genomes of bovine papillomavirus type 3 (BPV-3), bovine papillomavirus type 5 (BPV-5), equine papillomavirus (EQPV) and reindeer (Rangifer tarandus) papillomavirus (RPV) supports the notion that the pRB-binding motif is not ubiquitous among E7 proteins in the PV proteome. Key among the animal groups that lack the pRB-binding domain are the artiodactyl PVs, including European elk PV (EEPV), deer PV (DPV), reindeer PV (RPV), ovine PVs types 1 and 2 (OvPV-1 and -2) and bovine PVs 1, 2 and 5 (BPV-1, -2 and -5). Whereas the presence of the pRB-binding domain is normally associated with papillomas, the artiodactyl PVs are marked by the development of fibropapillomas on infection. Previous studies emphasized the role of E5 in the pathogenic mechanism of fibropapilloma development, but correlation between the lack of an E7 pRB-binding domain and the unique pathology of the artiodactyl PVs suggests a more complicated mechanism and an early evolutionary divergence from a pRB-binding ancestor.

scholarly journals A cytological approach to the role of guanine in determining quinacrine fluorescence response in eukaryotic chromosomes.

1982 ◽  
Vol 30 (12) ◽  
pp. 1289-1292 ◽  
Author(s):  
L Ferrucci ◽  
R Mezzanotte
Keyword(s):  
Drosophila Melanogaster ◽  
Mus Musculus ◽  
Banding Pattern ◽  
Drosophila Virilis ◽  
Primary Role ◽  
Chromosomal Dna ◽  
Metaphase Chromosomes ◽  
Fluorescence Response ◽  
Quinacrine Fluorescence

Photooxidation is believed to preferentially remove guanine (G) residues from chromosomal DNA. G interspersion, moreover, has been hypothesized as quenching quinacrine (Q) fluorescence in cytological preparations. Hence, we used photooxidation as a tool for inducing possible changes in the Q-banding pattern of Drosophila melanogaster, Drosophila virilis, and Mus musculus metaphase chromosomes. An enhanced Q fluorescence, which was particularly evident in certain chromosomal regions, was found. This finding would support the postulated primary role of G in determining Q bands in eukaryotic chromosomes.

scholarly journals Evolutionary Analysis of Candidate Non-Coding Elements Regulating Neurodevelopmental Genes in Vertebrates

2017 ◽  
Author(s):  
Francisco J. Novo
Keyword(s):  
Gene Networks ◽  
Evolutionary Biology ◽  
Developmental Stages ◽  
General Pattern ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Evolutionary Analysis ◽  
Enhancer Activity ◽  
Expression Of Genes ◽  
Peer Community

ABSTRACTMany non-coding regulatory elements conserved in vertebrates regulate the expression of genes involved in development and play an important role in the evolution of morphology through the rewiring of developmental gene networks. Available biological datasets allow the identification of non-coding regulatory elements with high confidence; furthermore, chromatin conformation data can be used to confirm enhancer-promoter interactions in specific tissue types and developmental stages. We have devised an analysis pipeline that integrates datasets about gene expression, enhancer activity, chromatin accessibility, epigenetic marks, and Hi-C contact frequencies in various brain tissues and developmental stages, leading to the identification of eight non-coding elements that might regulate the expression of three genes with important roles in brain development in vertebrates. We have then performed comparative sequence and microsynteny analyses in order to reconstruct the evolutionary history of the regulatory landscape around these genes; we observe a general pattern of ancient regulatory elements conserved across most vertebrate lineages, together with younger elements that appear to be mammal and primate innovations. This preprint has been reviewed and recommended by Peer Community In Evolutionary Biology (http://dx.doi.org/10.24072/pci.evolbiol.100035)

scholarly journals A reference map of murine cardiac transcription factor chromatin occupancy identifies dynamic and conserved enhancers

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Brynn N. Akerberg ◽  
Fei Gu ◽  
Nathan J. VanDusen ◽  
Xiaoran Zhang ◽  
Rui Dong ◽  
...  
Keyword(s):  
Heart Development ◽  
Molecular Mechanisms ◽  
Developmental Stages ◽  
Transcriptional Regulatory Network ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Mouse Heart ◽  
Transcriptional Enhancer ◽  
Enhancer Activity

Abstract Mapping the chromatin occupancy of transcription factors (TFs) is a key step in deciphering developmental transcriptional programs. Here we use biotinylated knockin alleles of seven key cardiac TFs (GATA4, NKX2-5, MEF2A, MEF2C, SRF, TBX5, TEAD1) to sensitively and reproducibly map their genome-wide occupancy in the fetal and adult mouse heart. These maps show that TF occupancy is dynamic between developmental stages and that multiple TFs often collaboratively occupy the same chromatin region through indirect cooperativity. Multi-TF regions exhibit features of functional regulatory elements, including evolutionary conservation, chromatin accessibility, and activity in transcriptional enhancer assays. H3K27ac, a feature of many enhancers, incompletely overlaps multi-TF regions, and multi-TF regions lacking H3K27ac retain conservation and enhancer activity. TEAD1 is a core component of the cardiac transcriptional network, co-occupying cardiac regulatory regions and controlling cardiomyocyte-specific gene functions. Our study provides a resource for deciphering the cardiac transcriptional regulatory network and gaining insights into the molecular mechanisms governing heart development.

scholarly journals Enhancer RNAs: Insights Into Their Biological Role

2019 ◽  
Vol 12 ◽  
pp. 251686571984609 ◽  
Author(s):  
Josué Cortés-Fernández de Lara ◽  
Rodrigo G Arzate-Mejía ◽  
Félix Recillas-Targa
Keyword(s):  
Functional Role ◽  
Transcriptional Activity ◽  
Noncoding Rnas ◽  
Chromatin Accessibility ◽  
Regulatory Proteins ◽  
Enhancer Activity ◽  
Regulate Gene Expression ◽  
Experimental Approaches ◽  
Pervasive Transcription

Enhancers play a central role in the transcriptional regulation of metazoans. Almost a decade ago, the discovery of their pervasive transcription into noncoding RNAs, termed enhancer RNAs (eRNAs), opened a whole new field of study. The presence of eRNAs correlates with enhancer activity; however, whether they act as functional molecules remains controversial. Here we review direct experimental evidence supporting a functional role of eRNAs in transcription and provide a general pipeline that could help in the design of experimental approaches to investigate the function of eRNAs. We propose that induction of transcriptional activity at enhancers promotes an increase in its activity by an RNA-mediated titration of regulatory proteins that can impact different processes like chromatin accessibility or chromatin looping. In a few cases, transcripts originating from enhancers have acquired specific molecular functions to regulate gene expression. We speculate that these transcripts are either nonannotated long noncoding RNAs (lncRNAs) or are evolving toward functional lncRNAs. Further work will be needed to comprehend better the biological activity of these transcripts.

scholarly journals Chromatin accessibility combined with enhancer clusters activation mediates heterogeneous response to dexamethasone in myeloma cells

2021 ◽  
Author(s):  
Victor GABORIT ◽  
Jonathan CRUARD ◽  
Catherine Guerin-Charbonnel ◽  
Jennifer Derrien ◽  
Jean-Baptiste Alberge ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Interaction Network ◽  
Chromatin Accessibility ◽  
Enhancer Activity ◽  
Myeloma Cells ◽  
Combinatorial Assembly ◽  
Induced Apoptosis ◽  
Combination Regimens

Glucocorticoids (GC) effects occur through binding to the GC receptor (GR) which, once translocated to the nucleus, binds to GC response elements (GREs) to activate or repress target genes. Among GCs, dexamethasone (Dex) is widely used in treatment of multiple myeloma (MM), mainly in combination regimens. However, despite a definite benefit, all patients relapse. Moreover, while GC efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive. To determine the functional role of GR binding in myeloma cells, we generated bulk and single cell multi-omic data and high-resolution contact maps of active enhancers and target genes. We show that a minority (6%) of GR binding sites are associated with enhancer activity gains and increased interaction loops. We find that enhancers contribute to regulate gene activity through combinatorial assembly of large stretches of enhancers and/or enhancer cliques. Furthermore, one enhancer, proximal to GR-responsive genes, is predominantly associated with increased chromatin accessibility and higher H3K27ac occupancy. Finally, we show that Dex exposure leads to co-accessibility changes between predominant enhancer and other regulatory regions of the interaction network. Notably, these epigenomic changes are associated with cell-to-cell transcriptional heterogeneity. As consequences, BIM critical for GR-induced apoptosis and CXCR4 protective from chemotherapy-induced apoptosis are rather upregulated in different cells. In summary, our work provides new insights into the molecular mechanisms involved in Dex escape.

scholarly journals MULTIPLE ALLELE APPROACH TO THE STUDY OF GENES IN DROSOPHILA MELANOGASTER THAT ARE INVOLVED IN IMAGINAL DISC DEVELOPMENT

Genetics ◽  
1978 ◽  
Vol 89 (2) ◽  
pp. 355-370 ◽  
Author(s):  
Allen Shearn ◽  
Grafton Hersperger ◽  
Evelyn Hersperger ◽  
Ellen Steward Pentz ◽  
Paul Denker
Keyword(s):  
Drosophila Melanogaster ◽  
Phenotypic Variation ◽  
Mutant Allele ◽  
Imaginal Disc ◽  
Reference Allele ◽  
Multiple Allele ◽  
Significant Difference ◽  
Chromosome Mutations ◽  
Cold Sensitive

ABSTRACT The phenotypes of five different lethal mutants of Drosophila melanogaster that have small imaginal discs were analyzed in detail. From these results, we inferred whether or not the observed imaginal disc phenotype resulted exclusively from a primary imaginal disc defect in each mutant. To examine the validity of these inferences, we employed a multiple-allele method. Lethal alleles of the five third-chromosome mutations were identified by screening EMS-treated chromosomes for those which fail to complement with a chromosome containing all five reference mutations. Twenty-four mutants were isolated from 13,197 treated chromosomes. Each of the 24 was then tested for complementation with each of the five reference mutants. There was no significant difference in the mutation frequencies at these five loci. The stage of lethality and the imaginal disc morphology of each mutant allele were compared to those of its reference allele in order to examine the range of defects to be found among lethal alleles of each locus. In addition, hybrids of the alleles were examined for intracistronic complementation. For two of the five loci, we detected no significant phenotypic variation among lethal alleles. We infer that each of the mutant alleles at these two loci cause expression of the null activity phenotype. However, for the three other loci, we did detect significant phenotypic variation among lethal alleles. In fact, one of the mutant alleles at each of these three loci causes no detectable imaginal disc defect. This demonstrates that attempting to assess the developmental role of a gene by studying a single mutant allele may lead to erroneous conclusions. As a byproduct of the mutagenesis procedure, we have isolated two dominant, cold-sensitive mutants.

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