scholarly journals Discovery of an autoimmunity-associated IL2RA enhancer by unbiased targeting of transcriptional activation

2016 ◽  
Author(s):  
Dimitre R. Simeonov ◽  
Benjamin G. Gowen ◽  
Mandy Boontanrart ◽  
Theodore Roth ◽  
Youjin Lee ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Transcriptional Activation ◽  
Gene Activation ◽  
Interleukin 2 ◽  
General Mechanism ◽  
Enhancer Activity ◽  
Extracellular Signals ◽  
Coding Regions ◽  
Cell Type Specific ◽  
Genomic Regions

The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell type-specific transcriptional programs and responses to specific extracellular cues 1-3. In order to understand the mechanisms by which non-coding genetic variation contributes to disease, systematic mapping of functional enhancers and their biological contexts is required. Here, we develop an unbiased discovery platform that can identify enhancers for a target gene without prior knowledge of their native functional context. We used tiled CRISPR activation (CRISPRa) to synthetically recruit transcription factors to sites across large genomic regions (>100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA (interleukin-2 receptor alpha; CD25). We identified several CRISPRa responsive elements (CaREs) with stimulation-dependent enhancer activity, including an IL2RA enhancer that harbors an autoimmunity risk variant. Using engineered mouse models and genome editing of human primary T cells, we found that sequence perturbation of the disease-associated IL2RA enhancer does not block IL2RA expression, but rather delays the timing of gene activation in response to specific extracellular signals. This work develops an approach to rapidly identify functional enhancers within non-coding regions, decodes a key human autoimmunity association, and suggests a general mechanism by which genetic variation can cause immune dysfunction.

scholarly journals Genetic variation of populations of Citrus psorosis virus

2006 ◽  
Vol 87 (10) ◽  
pp. 3097-3102 ◽  
Author(s):  
Susana Martín ◽  
María Laura García ◽  
Antonella Troisi ◽  
Luis Rubio ◽  
Gonzalo Legarreta ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Type Species ◽  
Protein Gene ◽  
Nucleotide Substitutions ◽  
Coding Regions ◽  
Citrus Psorosis Virus ◽  
Selection For ◽  
Genomic Regions ◽  
Two Populations ◽  
Amino Acid Sequence Conservation

Citrus psorosis virus (CPsV), the type species of genus Ophiovirus, has a segmented, negative-stranded RNA genome. We examined the population structure and genetic variation of CPsV in three coding regions located in RNAs 1, 2 and 3, analysing 22 isolates from Argentina, California, Florida, Italy and Spain. Most isolates contained a predominant sequence and some minor variants. Estimations of the genetic diversity and phylogenetic clustering of isolates disclosed two populations, one comprising isolates from Spain, Italy, Florida and California and the other including the Argentinean isolates. Isolate CPV-4 (from Texas) included for comparison was distant from both groups, suggesting that it belongs to a third group. The low ratio between non-synonymous and synonymous nucleotide substitutions indicated strong selection for amino acid sequence conservation, particularly in the coat protein gene. Incongruent phylogenetic relationships in different genomic regions suggested that exchange of genomic segments may have contributed to CPsV evolution.

scholarly journals Genetic variation in heat tolerance of the coral Platygyra daedalea offers the potential for adaptation to ocean warming

2020 ◽  
Author(s):  
Holland Elder ◽  
Virginia Weis ◽  
Jose Montalvo-Proano ◽  
Veronique J.L Mocellin ◽  
Andrew H. Baird ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Heat Stress ◽  
Heat Tolerance ◽  
Nucleotide Polymorphisms ◽  
Narrow Sense Heritability ◽  
Coding Regions ◽  
Genomic Tools ◽  
Coral Reef Ecosystems ◽  
Few Data ◽  
Genomic Regions

AbstractReef-building corals are foundational species in coral reef ecosystems and are threatened by many stressors including rising ocean temperatures. In 2015/16 and 2016/17, corals around the world experienced consecutive bleaching events and most coral populations are projected to experience temperatures above their current bleaching thresholds annually by 2050. Adaptation to higher temperatures is therefore necessary if corals are to persist in a warming future. While many aspects of heat stress have been well studied, few data are available for predicting the capacity for adaptive cross-generational responses in corals. To address this knowledge gap, we quantified the heritability and genetic variation associated with heat tolerance in Platygyra daedalea from the Great Barrier Reef (GBR). We tracked the survival of replicate quantitative genetic crosses (or families) of coral larvae from six parents in a heat stress selection experiment. We also identified allelic shifts in heat-selected survivors versus paired, non-selected controls of the same coral crosses. We estimated narrow sense heritability to be 0.66 and detected a total of 1,069 single nucleotide polymorphisms (SNPs) associated with heat tolerance. An overlap of 148 unique SNPs shared between experimental crosses indicates that specific genomic regions are responsible for heat tolerance of P. daedalea and some of these SNPs fall in coding regions. These findings suggest that this P. daedalea population has the genetic prerequisites for adaptation to increasing temperatures. This study also provides knowledge for the development of high throughput genomic tools to screen for variation within and across populations to harness or enhance adaptation through assisted gene flow and assisted migration.

scholarly journals Identification and prediction of developmental enhancers in sea urchin embryos

2021 ◽  
Author(s):  
Cesar Arenas-Mena ◽  
Sofija Miljovska ◽  
Sevinc Ercan ◽  
Tanvi Shashikant ◽  
Charles G. Danko ◽  
...  
Keyword(s):  
Sea Urchin ◽  
Transcriptional Activation ◽  
Functional Characterization ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Model Organisms ◽  
Enhancer Activity ◽  
Pol Ii ◽  
Sea Urchin Embryos ◽  
Genomic Regions

The transcription of developmental regulatory genes is often controlled by multiple cis-regulatory elements. The identification and functional characterization of distal regulatory elements remains challenging, even in tractable model organisms like sea urchins. We evaluate the use of chromatin accessibility, transcription and RNA Polymerase II for their ability to predict enhancer activity of genomic regions in sea urchin embryos. ATAC-seq, PRO-seq, and Pol II ChIP-seq from early and late blastula embryos are manually contrasted with experimental cis-regulatory analyses available in sea urchin embryos, with particular attention to common developmental regulatory elements known to have enhancer and silencer functions differentially deployed among embryonic territories. Using the three functional genomic data types, machine learning models are trained and tested to classify and quantitatively predict the enhancer activity of several hundred genomic regions previously validated with reporter constructs in vivo. Overall, chromatin accessibility and transcription have substantial power for predicting enhancer activity. For promoter-overlapping cis-regulatory elements in particular, the distribution of Pol II is the best predictor of enhancer activity in blastula embryos. Furthermore, ATAC- and PRO-seq predictive value is stage dependent for the promoter-overlapping subset. This suggests that the sequence of regulatory mechanisms leading to transcriptional activation have distinct relevance at different levels of the developmental gene regulatory hierarchy deployed during embryogenesis.

scholarly journals Cell type-dependent control of p53 transcription and enhancer activity by p63

2018 ◽  
Author(s):  
Gizem Karsli Uzunbas ◽  
Faraz Ahmed ◽  
Morgan A. Sammons
Keyword(s):  
Transcriptional Activation ◽  
Cellular Response ◽  
Cell Types ◽  
Regulatory Elements ◽  
Cell Type ◽  
P53 Family ◽  
Enhancer Activity ◽  
Response To Stress ◽  
Cell Type Specific ◽  
Stress Dependent

ABSTRACTTranscriptional activation by p53 provides powerful, organism-wide tumor suppression. In this work, we demonstrate that the p53-induced transcriptome varies based on cell type, reflects cell type-specific activities, and is considerably more broad than previously anticipated. This behavior is strongly influenced by p53 engagement with differentially active cell type-specific enhancers and promoters. In epithelial cell types, p53 activity is dependent on the p53 family member p63, which displays widespread enhancer binding. Notably, we demonstrate that p63 is required for epithelial enhancer identity including enhancers used by p53 during stress-dependent signaling. Loss of p63, but not p53, leads to site-specific depletion of enhancer-associated chromatin modifications, suggesting that p63 functions as an enhancer maintenance factor in epithelial cells. Additionally, a subset of epithelial-specific enhancers is dependent on the activity of p63 providing a direct link between lineage determination and enhancer structure. These data suggest a broad, cell-intrinsic mechanism for regulating the p53-dependent cellular response to stress through differential regulation ofcis-regulatory elements.

scholarly journals The Significance of Tetramerization in Promoter Recruitment by Stat5

1999 ◽  
Vol 19 (3) ◽  
pp. 1910-1918 ◽  
Author(s):  
Susan John ◽  
Uwe Vinkemeier ◽  
Elisabetta Soldaini ◽  
James E. Darnell ◽  
Warren J. Leonard
Keyword(s):  
Protein Interactions ◽  
Transcriptional Activation ◽  
Gene Activation ◽  
Interleukin 2 ◽  
Regulatory Region ◽  
Tryptophan Residue ◽  
Protein Protein Interactions ◽  
Tetramer Formation ◽  
Wide Range ◽  
The Individual

ABSTRACT Stat5a and Stat5b are rapidly activated by a wide range of cytokines and growth factors, including interleukin-2 (IL-2). We have previously shown that these signal transducers and activators of transcription (STAT proteins) are key regulatory proteins that bind to two tandem gamma interferon-activated site (GAS) motifs within an IL-2 response element (positive regulatory region III [PRRIII]) in the human IL-2Rα promoter. In this study, we demonstrate cooperative binding of Stat5 to PRRIII and explore the molecular basis underlying this cooperativity. We demonstrate that formation of a tetrameric Stat5 complex is essential for the IL-2-inducible activation of PRRIII. Stable tetramer formation of Stat5 is mediated through protein-protein interactions involving a tryptophan residue conserved in all STATs and a lysine residue in the Stat5 N-terminal domain (N domain). The functional importance of tetramer formation is shown by the decreased levels of transcriptional activation associated with mutations in these residues. Moreover, the requirement for STAT protein-protein interactions for gene activation from a promoter with tandemly linked GAS motifs can be relieved by strengthening the avidity of protein-DNA interactions for the individual binding sites. Taken together, these studies demonstrate that a dimeric but tetramerization-deficient Stat5 protein can activate only a subset of target sites. For functional activity on a wider range of potential recognition sites, N-domain-mediated oligomerization is essential.

scholarly journals Fibroblast Growth Factor Receptor-1 (FGFR1) Nuclear Dynamics Reveal a Novel Mechanism in Transcription Control

2009 ◽  
Vol 20 (9) ◽  
pp. 2401-2412 ◽  
Author(s):  
Star M. Dunham-Ems ◽  
Yu-Wei Lee ◽  
Ewa K. Stachowiak ◽  
Haridas Pudavar ◽  
Peter Claus ◽  
...  
Keyword(s):  
Nuclear Matrix ◽  
Transcriptional Activation ◽  
Gene Activation ◽  
Growth Factor Receptor ◽  
General Mechanism ◽  
Creb Binding Protein ◽  
Transcription Control ◽  
Nuclear Dynamics ◽  
Transcription Inhibitors ◽  
Mobile Population

Nuclear FGFR1 acts as a developmental gene regulator in cooperation with FGF-2, RSK1, and CREB-binding protein (CBP). FRAP analysis revealed three nuclear FGFR1 populations: i) a fast mobile, ii) a slower mobile population reflecting chromatin-bound FGFR1, and iii) an immobile FGFR1 population associated with the nuclear matrix. Factors (cAMP, CBP) that induce FGFR1-mediated gene activation shifted FGFR1 from the nuclear matrix (immobile) to chromatin (slow) and reduced the movement rate of the chromatin-bound population. Transcription inhibitors accelerated FGFR1 movement; the content of the chromatin-bound slow FGFR1 decreased, whereas the fast population increased. The transcriptional activation appears to involve conversion of the immobile matrix-bound and the fast nuclear FGFR1 into a slow chromatin-binding population through FGFR1's interaction with CBP, RSK1, and the high-molecular-weight form of FGF-2. Our findings support a general mechanism in which gene activation is governed by protein movement and collisions with other proteins and nuclear structures.

scholarly journals LncRNA:DNA triplex-forming sites are positioned at specific areas of genome organization and are predictors for Topologically Associated Domains

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Benjamin Soibam ◽  
Ayzhamal Zhamangaraeva
Keyword(s):  
Genome Organization ◽  
Chromatin Organization ◽  
Ctcf Binding ◽  
General Mechanism ◽  
Promoter Regions ◽  
Cellular Processes ◽  
A Genome ◽  
Topologically Associated Domains ◽  
Multiple Cell ◽  
Genomic Regions

Abstract Background Chromosomes are organized into units called topologically associated domains (TADs). TADs dictate regulatory landscapes and other DNA-dependent processes. Even though various factors that contribute to the specification of TADs have been proposed, the mechanism is not fully understood. Understanding the process for specification and maintenance of these units is essential in dissecting cellular processes and disease mechanisms. Results In this study, we report a genome-wide study that considers the idea of long noncoding RNAs (lncRNAs) mediating chromatin organization using lncRNA:DNA triplex-forming sites (TFSs). By analyzing the TFSs of expressed lncRNAs in multiple cell lines, we find that they are enriched in TADs, their boundaries, and loop anchors. However, they are evenly distributed across different regions of a TAD showing no preference for any specific portions within TADs. No relationship is observed between the locations of these TFSs and CTCF binding sites. However, TFSs are located not just in promoter regions but also in intronic, intergenic, and 3’UTR regions. We also show these triplex-forming sites can be used as predictors in machine learning models to discriminate TADs from other genomic regions. Finally, we compile a list of important “TAD-lncRNAs” which are top predictors for TADs identification. Conclusions Our observations advocate the idea that lncRNA:DNA TFSs are positioned at specific areas of the genome organization and are important predictors for TADs. LncRNA:DNA triplex formation most likely is a general mechanism of action exhibited by some lncRNAs, not just for direct gene regulation but also to mediate 3D chromatin organization.

scholarly journals Inferring time series chromatin states for promoter-enhancer pairs based on Hi-C data

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Henriette Miko ◽  
Yunjiang Qiu ◽  
Bjoern Gaertner ◽  
Maike Sander ◽  
Uwe Ohler
Keyword(s):  
Time Series ◽  
Histone Modifications ◽  
Gene Activation ◽  
Expectation Maximization Algorithm ◽  
Chromatin State ◽  
Open Chromatin ◽  
Multiple Time ◽  
Enhancer Activity ◽  
Chromatin States ◽  
Multiple Time Points

Abstract Background Co-localized combinations of histone modifications (“chromatin states”) have been shown to correlate with promoter and enhancer activity. Changes in chromatin states over multiple time points (“chromatin state trajectories”) have previously been analyzed at promoter and enhancers separately. With the advent of time series Hi-C data it is now possible to connect promoters and enhancers and to analyze chromatin state trajectories at promoter-enhancer pairs. Results We present TimelessFlex, a framework for investigating chromatin state trajectories at promoters and enhancers and at promoter-enhancer pairs based on Hi-C information. TimelessFlex extends our previous approach Timeless, a Bayesian network for clustering multiple histone modification data sets at promoter and enhancer feature regions. We utilize time series ATAC-seq data measuring open chromatin to define promoters and enhancer candidates. We developed an expectation-maximization algorithm to assign promoters and enhancers to each other based on Hi-C interactions and jointly cluster their feature regions into paired chromatin state trajectories. We find jointly clustered promoter-enhancer pairs showing the same activation patterns on both sides but with a stronger trend at the enhancer side. While the promoter side remains accessible across the time series, the enhancer side becomes dynamically more open towards the gene activation time point. Promoter cluster patterns show strong correlations with gene expression signals, whereas Hi-C signals get only slightly stronger towards activation. The code of the framework is available at https://github.com/henriettemiko/TimelessFlex. Conclusions TimelessFlex clusters time series histone modifications at promoter-enhancer pairs based on Hi-C and it can identify distinct chromatin states at promoter and enhancer feature regions and their changes over time.

scholarly journals Distinct Responses of Arabidopsis Telomeres and Transposable Elements to Zebularine Exposure

2021 ◽  
Vol 22 (1) ◽  
pp. 468
Author(s):  
Klára Konečná ◽  
Pavla Polanská Sováková ◽  
Karin Anteková ◽  
Jiří Fajkus ◽  
Miloslava Fojtová
Keyword(s):  
Transposable Elements ◽  
Transcriptional Activation ◽  
Genome Stability ◽  
Cytosine Methylation ◽  
Individual Variability ◽  
Correlated Response ◽  
Telomere Shortening ◽  
Treatment Changes ◽  
Telomere Homeostasis ◽  
Genomic Regions

Involvement of epigenetic mechanisms in the regulation of telomeres and transposable elements (TEs), genomic regions with the protective and potentially detrimental function, respectively, has been frequently studied. Here, we analyzed telomere lengths in Arabidopsis thaliana plants of Columbia, Landsberg erecta and Wassilevskija ecotypes exposed repeatedly to the hypomethylation drug zebularine during germination. Shorter telomeres were detected in plants growing from seedlings germinated in the presence of zebularine with a progression in telomeric phenotype across generations, relatively high inter-individual variability, and diverse responses among ecotypes. Interestingly, the extent of telomere shortening in zebularine Columbia and Wassilevskija plants corresponded to the transcriptional activation of TEs, suggesting a correlated response of these genomic elements to the zebularine treatment. Changes in lengths of telomeres and levels of TE transcripts in leaves were not always correlated with a hypomethylation of cytosines located in these regions, indicating a cytosine methylation-independent level of their regulation. These observations, including differences among ecotypes together with distinct dynamics of the reversal of the disruption of telomere homeostasis and TEs transcriptional activation, reflect a complex involvement of epigenetic processes in the regulation of crucial genomic regions. Our results further demonstrate the ability of plant cells to cope with these changes without a critical loss of the genome stability.

scholarly journals Genetic variation in recombination rate in the pig

2021 ◽  
Vol 53 (1) ◽  
Author(s):  
Martin Johnsson ◽  
Andrew Whalen ◽  
Roger Ros-Freixedes ◽  
Gregor Gorjanc ◽  
Ching-Yi Chen ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Recombination Rate ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Genetic Material ◽  
A Genome ◽  
Pig Genome ◽  
Genetic Length ◽  
Trait Locus ◽  
Genomic Regions

Abstract Background Meiotic recombination results in the exchange of genetic material between homologous chromosomes. Recombination rate varies between different parts of the genome, between individuals, and is influenced by genetics. In this paper, we assessed the genetic variation in recombination rate along the genome and between individuals in the pig using multilocus iterative peeling on 150,000 individuals across nine genotyped pedigrees. We used these data to estimate the heritability of recombination and perform a genome-wide association study of recombination in the pig. Results Our results confirmed known features of the recombination landscape of the pig genome, including differences in genetic length of chromosomes and marked sex differences. The recombination landscape was repeatable between lines, but at the same time, there were differences in average autosome-wide recombination rate between lines. The heritability of autosome-wide recombination rate was low but not zero (on average 0.07 for females and 0.05 for males). We found six genomic regions that are associated with recombination rate, among which five harbour known candidate genes involved in recombination: RNF212, SHOC1, SYCP2, MSH4 and HFM1. Conclusions Our results on the variation in recombination rate in the pig genome agree with those reported for other vertebrates, with a low but nonzero heritability, and the identification of a major quantitative trait locus for recombination rate that is homologous to that detected in several other species. This work also highlights the utility of using large-scale livestock data to understand biological processes.

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