scholarly journals Putative bovine topological association domains and CTCF binding motifs can reduce the search space for causative regulatory variants of complex traits

BMC Genomics ◽  
2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Min Wang ◽  
Timothy P. Hancock ◽  
Amanda J. Chamberlain ◽  
Christy J. Vander Jagt ◽  
Jennie E. Pryce ◽  
...  
Keyword(s):  
Complex Traits ◽  
Search Space ◽  
Ctcf Binding ◽  
Binding Motifs ◽  
Regulatory Variants

scholarly journals Putative bovine topological association domains and CTCF binding motifs can reduce the search space for causative regulatory variants of complex traits

2018 ◽  
Author(s):  
Min Wang ◽  
Timothy P Hancock ◽  
Amanda J. Chamberlain ◽  
Christy J. Vander Jagt ◽  
Jennie E Pryce ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Bovine Genome ◽  
Search Space ◽  
Ctcf Binding ◽  
P Value ◽  
Trna Genes ◽  
Specific Expression ◽  
Binding Motifs ◽  
Regulatory Variants

AbstractBackgroundTopological association domains (TADs) are chromosomal domains characterised by frequent internal DNA-DNA interactions. The transcription factor CTCF binds to conserved DNA sequence patterns called CTCF binding motifs to either prohibit or facilitate chromosomal interactions. TADs and CTCF binding motifs control gene expression, but they are not yet well defined in the bovine genome. In this paper, we sought to improve the annotation of bovine TADs and CTCF binding motifs, and assess whether the new annotation can reduce the search space for cis-regulatory variants.ResultsWe used genomic synteny to map TADs and CTCF binding motifs from humans, mice, dogs and macaques to the bovine genome. We found that our mapped TADs exhibited the same hallmark properties of those sourced from experimental data, such as housekeeping gene, tRNA genes, CTCF binding motifs, SINEs, H3K4me3 and H3K27ac. Then we showed that runs of genes with the same pattern of allele-specific expression (ASE) (either favouring paternal or maternal allele) were often located in the same TAD or between the same conserved CTCF binding motifs. Analyses of variance showed that when averaged across all bovine tissues tested, TADs explained 14% of ASE variation (standard deviation, SD: 0.056), while CTCF explained 27% (SD: 0.078). Furthermore, we showed that the quantitative trait loci (QTLs) associated with gene expression variation (eQTLs) or ASE variation (aseQTLs), which were identified from mRNA transcripts from 141 lactating cows’ white blood and milk cells, were highly enriched at putative bovine CTCF binding motifs. The most significant aseQTL and eQTL for each genic target were located within the same TAD as the gene more often than expected (Chi-Squared test P-value ≤ 0.001).ConclusionsOur results suggest that genomic synteny can be used to functionally annotate conserved transcriptional components, and provides a tool to reduce the search space for causative regulatory variants in the bovine genome.

scholarly journals Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes

2015 ◽  
Vol 112 (47) ◽  
pp. E6456-E6465 ◽  
Author(s):  
Adrian L. Sanborn ◽  
Suhas S. P. Rao ◽  
Su-Chen Huang ◽  
Neva C. Durand ◽  
Miriam H. Huntley ◽  
...  
Keyword(s):  
Genome Editing ◽  
Binding Sites ◽  
Physical Structure ◽  
Ctcf Binding ◽  
Binding Motifs ◽  
Physical Simulations ◽  
Chromatin Folding ◽  
Mammalian Genomes ◽  
Single Base Pair ◽  
Fractal Globule

We recently used in situ Hi-C to create kilobase-resolution 3D maps of mammalian genomes. Here, we combine these maps with new Hi-C, microscopy, and genome-editing experiments to study the physical structure of chromatin fibers, domains, and loops. We find that the observed contact domains are inconsistent with the equilibrium state for an ordinary condensed polymer. Combining Hi-C data and novel mathematical theorems, we show that contact domains are also not consistent with a fractal globule. Instead, we use physical simulations to study two models of genome folding. In one, intermonomer attraction during polymer condensation leads to formation of an anisotropic “tension globule.” In the other, CCCTC-binding factor (CTCF) and cohesin act together to extrude unknotted loops during interphase. Both models are consistent with the observed contact domains and with the observation that contact domains tend to form inside loops. However, the extrusion model explains a far wider array of observations, such as why loops tend not to overlap and why the CTCF-binding motifs at pairs of loop anchors lie in the convergent orientation. Finally, we perform 13 genome-editing experiments examining the effect of altering CTCF-binding sites on chromatin folding. The convergent rule correctly predicts the affected loops in every case. Moreover, the extrusion model accurately predicts in silico the 3D maps resulting from each experiment using only the location of CTCF-binding sites in the WT. Thus, we show that it is possible to disrupt, restore, and move loops and domains using targeted mutations as small as a single base pair.

scholarly journals CTCF Binding Sites in the Herpes Simplex Virus 1 Genome Display Site-Specific CTCF Occupation, Protein Recruitment, and Insulator Function

2018 ◽  
Vol 92 (8) ◽  
pp. e00156-18 ◽  
Author(s):  
Shannan D. Washington ◽  
Farhana Musarrat ◽  
Monica K. Ertel ◽  
Gregory L. Backes ◽  
Donna M. Neumann
Keyword(s):  
Herpes Simplex ◽  
Binding Sites ◽  
Ctcf Binding ◽  
Herpes Simplex Virus 1 ◽  
Binding Motifs ◽  
Site Specific ◽  
Specific Manner ◽  
Simplex Virus ◽  
Protein Recruitment ◽  
Hsv 1

ABSTRACTThere are seven conserved CTCF binding domains in the herpes simplex virus 1 (HSV-1) genome. These binding sites individually flank the latency-associated transcript (LAT) and the immediate early (IE) gene regions, suggesting that CTCF insulators differentially control transcriptional domains in HSV-1 latency. In this work, we show that two CTCF binding motifs in HSV-1 display enhancer blocking in a cell-type-specific manner. We found that CTCF binding to the latent HSV-1 genome was LAT dependent and that the quantity of bound CTCF was site specific. Following reactivation, CTCF eviction was dynamic, suggesting that each CTCF site was independently regulated. We explored whether CTCF sites recruit the polycomb-repressive complex 2 (PRC2) to establish repressive domains through a CTCF-Suz12 interaction and found that Suz12 colocalized to the CTCF insulators flanking the ICP0 and ICP4 regions and, conversely, was removed at early times postreactivation. Collectively, these data support the idea that CTCF sites in HSV-1 are independently regulated and may contribute to lytic-latent HSV-1 control in a site-specific manner.IMPORTANCEThe role of chromatin insulators in DNA viruses is an area of interest. It has been shown in several beta- and gammaherpesviruses that insulators likely control the lytic transcriptional profile through protein recruitment and through the formation of three-dimensional (3D) chromatin loops. The ability of insulators to regulate alphaherpesviruses has been understudied to date. The alphaherpesvirus HSV-1 has seven conserved insulator binding motifs that flank regions of the genome known to contribute to the establishment of latency. Our work presented here contributes to the understanding of how insulators control transcription of HSV-1.

scholarly journals networkGWAS: A network-based approach for genome-wide association studies in structured populations

2021 ◽  
Author(s):  
Giulia Muzio ◽  
Leslie O'Bray ◽  
Laetitia Meng-Papaxanthos ◽  
Juliane Klatt ◽  
Karsten Borgwardt
Keyword(s):  
Genetic Markers ◽  
Complex Traits ◽  
Multiple Testing ◽  
Association Studies ◽  
Search Space ◽  
Structured Populations ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Multiple Testing Correction ◽  
Genome Wide

While the search for associations between genetic markers and complex traits has discovered tens of thousands of trait-related genetic variants, the vast majority of these only explain a tiny fraction of observed phenotypic variation. One possible strategy to detect stronger associations is to aggregate the effects of several genetic markers and to test entire genes, pathways or (sub)networks of genes for association to a phenotype. The latter, network-based genome-wide association studies, in particular suffers from a huge search space and an inherent multiple testing problem. As a consequence, current approaches are either based on greedy feature selection, thereby risking that they miss relevant associations, and/or neglect doing a multiple testing correction, which can lead to an abundance of false positive findings. To address the shortcomings of current approaches of network-based genome-wide association studies, we propose <tt>networkGWAS</tt>, a computationally efficient and statistically sound approach to gene-based genome-wide association studies based on mixed models and neighborhood aggregation. It allows for population structure correction and for well-calibrated p-values, which we obtain through a block permutation scheme. <tt>networkGWAS</tt> successfully detects known or plausible associations on simulated rare variants from H. sapiens data as well as semi-simulated and real data with common variants from A. thaliana and enables the systematic combination of gene-based genome-wide association studies with biological network information.

scholarly journals Accurate eQTL prioritization with an ensemble-based framework

2016 ◽  
Author(s):  
Haoyang Zeng ◽  
Matthew D. Edwards ◽  
Yuchun Guo ◽  
David K. Gifford
Keyword(s):  
Complex Traits ◽  
Sequence Variants ◽  
Eqtl Analysis ◽  
Reporter Expression ◽  
Expression Change ◽  
Computational Framework ◽  
Regulatory Variants ◽  
Genome Interpretation ◽  
Allele Specific ◽  
Reporter Assays

AbstractExpression quantitative trait loci (eQTL) analysis links sequence variants with gene expression change and serves as a successful approach to fine-map variants causal for complex traits and understand their pathogenesis. In this work, we present an ensemble-based computational framework, EnsembleExpr, for eQTL prioritization. When trained on data from massively parallel reporter assays (MPRA), EnsembleExpr accurately predicts reporter expression levels from DNA sequence and identifies sequence variants that exhibit significant allele-specific reporter expression. This framework achieved the best performance in the “eQTL-causal SNPs” open challenge in the Fourth Critical Assessment of Genome Interpretation (CAGI 4). We envision EnsembleExpr to be a powerful resource for interpreting non-coding regulatory variants and prioritizing disease-associated mutations for downstream validation.

scholarly journals Massively parallel identification of causal variants underlying gene expression differences in a yeast cross

2020 ◽  
Author(s):  
Kaushik Renganaath ◽  
Rocky Cheung ◽  
Laura Day ◽  
Sriram Kosuri ◽  
Leonid Kruglyak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Sites ◽  
Complex Traits ◽  
Massively Parallel ◽  
Epistatic Interactions ◽  
Regulatory Variants ◽  
Causal Variants ◽  
Massively Parallel Reporter Assay ◽  
Regulatory Dna ◽  
Affect Gene Expression

AbstractSequence variation in regulatory DNA alters gene expression and shapes genetically complex traits. However, the identification of individual, causal regulatory variants is challenging. Here, we used a massively parallel reporter assay to measure the cis-regulatory consequences of 5,832 natural DNA variants in the promoters of 2,503 genes in the yeast Saccharomyces cerevisiae. We identified 451 causal variants, which underlie genetic loci known to affect gene expression. Several promoters harbored multiple causal variants. In five promoters, pairs of variants showed non-additive, epistatic interactions. Causal variants were enriched at conserved nucleotides, tended to have low derived allele frequency, and were depleted from promoters of essential genes, which is consistent with the action of negative selection. Causal variants were also enriched for alterations in transcription factor binding sites. Models integrating these features provided modest, but statistically significant, ability to predict causal variants. This work revealed a complex molecular basis for cis-acting regulatory variation.

scholarly journals CTCF Expression and Dynamic Motif Accessibility Modulates Epithelial–Mesenchymal Gene Expression

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 209
Author(s):  
Kelsey S. Johnson ◽  
Shaimaa Hussein ◽  
Priyanka Chakraborty ◽  
Arvind Muruganantham ◽  
Sheridan Mikhail ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Mesenchymal Transition ◽  
Function Analysis ◽  
Chromatin Accessibility ◽  
Ctcf Binding ◽  
Breast Cancer Cell Lines ◽  
Loss Of Function ◽  
Binding Motifs ◽  
Mesenchymal Transition ◽  
Partial States

Epithelial–mesenchymal transition (EMT) and its reversal, mesenchymal–epithelial transition (MET) drive tissue reorganization critical for early development. In carcinomas, processing through EMT, MET, or partial states promotes migration, invasion, dormancy, and metastatic colonization. As a reversible process, EMT is inherently regulated at epigenetic and epigenomic levels. To understand the epigenomic nature of reversible EMT and its partial states, we characterized chromatin accessibility dynamics, transcriptomic output, protein expression, and cellular phenotypes during stepwise reversible EMT. We find that the chromatin insulating protein machinery, including CTCF, is suppressed and re-expressed, coincident with broad alterations in chromatin accessibility, during EMT/MET, and is lower in triple-negative breast cancer cell lines with EMT features. Through an analysis of chromatin accessibility using ATAC-seq, we identify that early phases of EMT are characterized by enrichment for AP-1 family member binding motifs, but also by a diminished enrichment for CTCF binding motifs. Through a loss-of-function analysis, we demonstrate that the suppression of CTCF alters cellular plasticity, strengthening the epithelial phenotype via the upregulation of epithelial markers E-cadherin/CDH1 and downregulation of N-cadherin/CDH2. Conversely, the upregulation of CTCF leads to the upregulation of EMT gene expression and an increase in mesenchymal traits. These findings are indicative of a role of CTCF in regulating epithelial–mesenchymal plasticity and gene expression.

scholarly journals Epithelial-mesenchymal plasticity through loss of CTCF motif accessibility and protein expression

2021 ◽  
Author(s):  
Kelsey S Johnson ◽  
Shaimaa Hussein ◽  
Priyanka Chakraborty ◽  
Arvind Muruganantham ◽  
Sheridan Mikhail ◽  
...  
Keyword(s):  
Protein Expression ◽  
Epithelial Mesenchymal Transition ◽  
Function Analysis ◽  
Chromatin Accessibility ◽  
Ctcf Binding ◽  
Breast Cancer Cell Lines ◽  
Loss Of Function ◽  
Binding Motifs ◽  
Mesenchymal Transition ◽  
Partial States

Epithelial-mesenchymal transition (EMT) and its reversal, mesenchymal-epithelial transition (MET) drive tissue reorganization critical for early development. In carcinomas, processing through EMT, MET or partial states promotes migration, invasion, dormancy, and metastatic colonization. As a reversible process, EMT is inherently regulated at epigenetic and epigenomic levels. To understand the epigenomic nature of reversible EMT and its partial states, we characterized chromatin accessibility dynamics, transcriptomic output, protein expression, and cellular phenotypes during stepwise reversible EMT. We found that the chromatin insulating protein machinery, including CTCF, is suppressed and re-expressed, coincident with broad alterations in chromatin accessibility, during EMT/MET and is lower in triple-negative breast cancer cell lines with EMT features. Through analysis of chromatin accessibility using ATAC-seq, we identify that early phases of EMT are characterized by enrichment for AP-1 family member binding motifs but also by diminished enrichment for CTCF binding motifs. Through loss-of-function analysis we demonstrate that suppression of CTCF alters cellular plasticity, facilitating entrance into a partial EMT state. These findings are indicative of a role of CTCF and chromatin reorganization for epithelial-mesenchymal plasticity.

scholarly journals MicroRNA binding site variation is enriched in psychiatric disorders

2021 ◽  
Author(s):  
Michael P. Geaghan ◽  
William R. Reay ◽  
Murray J. Cairns
Keyword(s):  
Binding Site ◽  
Psychiatric Disorders ◽  
Complex Traits ◽  
Target Genes ◽  
Environmental Influence ◽  
Regulatory Sequences ◽  
Rna Sequences ◽  
Regulatory Variants ◽  
Site Variation ◽  
Significant Enrichment

AbstractPsychiatric disorders and other complex traits have a polygenic architecture, often associated with dozens or even hundreds of independent genomic loci. As each of these have a relatively small influence on the trait, the dissection of their biological components is a non-trivial task. For psychiatric disorders in particular, the majority of associated loci lie within non-coding regions of the genome, suggesting that most of the genetic risk for disease originates from the disruption of regulatory sequences. While previously exploration of the heritability of these sequences has focused on variants that modify DNA elements, those that alter cis-acting RNA sequences, such as miRNA binding sites, are also likely to have a significant impact in these disorders. MiRNA have already been shown to be dysregulated in these disorders through both genetic and environmental influence, so it is reasonable to suspect their target genes may also be affected by common variation. In this study, we investigated the distribution of miRNA binding site variants (MBSVs) predicted to alter miRNA binding affinity in psychiatric disorders and observed significant enrichment in schizophrenia, depression, bipolar disorder, and anorexia nervosa. We also observed significant enrichment of MBSVs in genes targeted by several miRNA families, including miR-335-5p, miR-21-5p/590-5p, miR-361-5p, and miR-557 in both schizophrenia and depression, and nominally significant enrichment of MBSV for miR-323b-3p in schizophrenia. We also identified a significant association between MBSVs in gene sets involved in regulation of the synapse and synaptic depression in schizophrenia. While these observations support the role of miRNA in the pathophysiology of psychiatric disorders, we also observed significant association of MBSVs in other complex traits suggesting that MBSVs are an important class of regulatory variants that have functional implications for many disorders.

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