topological domains
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2022 ◽  
Vol 16 (1) ◽  
Author(s):  
Kim Philipp Jablonski ◽  
Leopold Carron ◽  
Julien Mozziconacci ◽  
Thierry Forné ◽  
Marc-Thorsten Hütt ◽  
...  

Abstract Background Genome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in three-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically associating domains (TADs) and their borders. Results For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e., the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases displays such a preferential localization of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that localization of risk loci in TAD borders differs between cancers and non-cancer diseases. Furthermore, different TAD border enrichments are observed in embryonic stem cells and differentiated cells, consistent with changes in topological domains along embryogenesis and delineating their contribution to disease risk. Conclusions Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with an effect on an individual gene, the other acting in interplay with 3D genome organization.


2021 ◽  
Vol 71 (6) ◽  
pp. 2091-94
Author(s):  
Ambreen Javed ◽  
Gulshan Ara Trali ◽  
Hassan Burair Abbas ◽  
Alia Sadiq

Objective: To predict the tertiary structure of human interferon alpha/beta receptor 2 protein. Study Design: Structure prediction by using bio informatics tools. Place and Duration of Study: Department of Biochemistry, Swat Medical College (STMC), Saidu Shareef, Swat, Pakistan, from Aug 2019 to Dec 2019. Methodology: All protein sequences of human interferon alpha/beta receptor 2 (isoforma, b and c) (IFNAR-2) were retrieved through the BLAST search (The Basic Local Alignment Search Tool) from available databases ‘NCBI’ (National Centre for Biotechnology Information) and ‘Uni Prot KB’ (The Universal Protein Resource). Sequence alignment was conducted by using Clustal Omega, to get the consensus sequence for IFNAR-2 protein. Consensus protein sequence of human IFNAR-2 was used for the prediction of the three-dimensional structure by employing Swiss-Model Server. Moreover, subcellular localization analysis was also performed by using CELLO2GO program. Results: Structural model of human IFNAR-2 protein was predicted and evaluated by Ramachandran dimension. Cellular localization of tertiary topological domains of the predicted models were revealed probability of localization of IFNAR-2 protein (isoform a, b & c) is highest in the plasma membrane due to the presence of the transmembrane alpha helical regions. Conclusion: This study predicted the tertiary structural dimensions of human IFNAR-2 protein, including the specific topological domains that contribute towards the subcellular compartmentalization and functional characteristics.


2021 ◽  
Author(s):  
Willem Vanderlinden ◽  
Enrico Skoruppa ◽  
Pauline J. Kolbeck ◽  
Enrico Carlon ◽  
Jan Lipfert

DNA supercoiling is a key regulatory mechanism that orchestrates DNA readout, recombination, and genome maintenance. DNA-binding proteins often mediate these processes by bringing two distant DNA sites together, thereby inducing (transient) topological domains. In order to understand the dynamics and molecular architecture of protein induced topological domains in DNA, quantitative and time-resolved approaches are required. Here we present a methodology to determine the size and dynamics of topological domains in supercoiled DNA in real-time and at the single molecule level. Our approach is based on quantifying the extension fluctuations -in addition to the mean extension- of supercoiled DNA in magnetic tweezers. Using a combination of high-speed magnetic tweezers experiments, Monte Carlo simulations, and analytical theory, we map out the dependence of DNA extension fluctuations as a function of supercoiling density and external force. We find that in the plectonemic regime the extension variance increases linearly with increasing supercoiling density and show how this enables us to determine the formation and size of topological domains. In addition, we demonstrate how transient (partial) dissociation of DNA bridging proteins results in dynamic sampling of different topological states, which allows us to deduce the torsional stiffness of the plectonemic state and the kinetics of protein-plectoneme interactions. We expect our approach to enable quantification of the dynamics and reaction pathways of DNA processing enzymes and motor proteins, in the context of physiologically relevant forces and supercoiling densities.


2021 ◽  
Author(s):  
Niels J. Rinzema ◽  
Konstantinos Sofiadis ◽  
Sjoerd J. D. Tjalsma ◽  
Marjon J.A.M. Verstegen ◽  
Yuva Oz ◽  
...  

ABSTRACTDevelopmental gene expression is often controlled by distal tissue-specific enhancers. Enhancer action is restricted to topological chromatin domains, typically formed by cohesin-mediated loop extrusion between CTCF-associated boundaries. To better understand how individual regulatory DNA elements form topological domains and control expression, we used a bottom-up approach, building active regulatory landscapes of different sizes in inactive chromatin. We demonstrate that transcriptional output and protection against gene silencing reduces with increased enhancer distance, but that enhancer contact frequencies alone do not dictate transcription activity. The enhancer recruits cohesin to stimulate the formation of local chromatin contact domains and activate flanking CTCF sites for engagement in chromatin looping. Small contact domains can support strong and stable expression of distant genes. The enhancer requires transcription factors and mediator to activate genes over all distance ranges, but relies on cohesin exclusively for the activation of distant genes. Our work supports a model that assigns two functions to enhancers: its classic role to stimulate transcription initiation and elongation from target gene promoters and a role to recruit cohesin for the creation of contact domains, the engagement of flanking CTCF sites in chromatin looping, and the activation of distal target genes.


2021 ◽  
Author(s):  
Kim Philipp Jablonski ◽  
Leopold Carron ◽  
Julien Mozziconacci ◽  
Thierry Forné ◽  
Marc-Thorsten Hütt ◽  
...  

Abstract Background Genome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in 3-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically-associating domains (TADs) and their borders. Results For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e. the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases displays such a preferential localization of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that localization of risk loci in TAD borders differ between cancers and non-cancer diseases. Furthermore, different TAD border enrichments are observed in embryonic stem cells and differentiated cells, consistent with changes in topological domains along embryogenesis and delineating their contribution to disease risk. Conclusions Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically-insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with a direct effect on an individual gene, the other acting in interplay with 3D genome organization.


2021 ◽  
Author(s):  
Kim Philipp Jablonski ◽  
Leopold Carron ◽  
Julien Mozziconacci ◽  
Thierry Forné ◽  
Marc-Thorsten Hütt ◽  
...  

Genome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in 3-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically-associating domains (TADs) and their borders. For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e. the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases display such a preferential location of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that TAD border enrichment in risk loci differ between cancers and non-cancer diseases. Different TAD border enrichments are observed in embryonic stem cells and differentiated cells, which agrees with an evolution along embryogenesis of the 3D genome organization into topological domains. Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically-insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with a direct effect on an individual gene, the other acting in interplay with 3D genome organization.


2021 ◽  
Author(s):  
Georgi K. Marinov ◽  
Alexandro E. Trevino ◽  
Tingting Xiang ◽  
Anshul Kundaje ◽  
Arthur R. Grossman ◽  
...  

AbstractDinoflagellate chromosomes represent a unique evolutionary experiment, as they exist in a permanently condensed, liquid crystalline state; are not packaged by histones; and contain genes organized into tandem gene arrays, with minimal transcriptional regulation. We analyze the three-dimensional genome of Breviolum minutum, and find large topological domains (dinoflagellate topologically associating domains, which we term ‘dinoTADs’) without chromatin loops, which are demarcated by convergent gene array boundaries. Transcriptional inhibition disrupts dinoTADs, implicating transcription-induced supercoiling as the primary topological force in dinoflagellates.


Author(s):  
Gang Liu ◽  
Zhenhao Liu ◽  
Xiaomeng Sun ◽  
Xiaoqiong Xia ◽  
Yunhe Liu ◽  
...  

DNA methylation dysregulation during carcinogenesis has been widely discussed in recent years. However, the pan-cancer DNA methylation biomarkers and corresponding biological mechanisms were seldom investigated. We identified differentially methylated sites and regions from 5,056 The Cancer Genome Atlas (TCGA) samples across 10 cancer types and then validated the findings using 48 manually annotated datasets consisting of 3,394 samples across nine cancer types from Gene Expression Omnibus (GEO). All samples’ DNA methylation profile was evaluated with Illumina 450K microarray to narrow down the batch effect. Nine regions were identified as commonly differentially methylated regions across cancers in TCGA and GEO cohorts. Among these regions, a DNA fragment consisting of ∼1,400 bp detected inside the HOXA locus instead of the boundary may relate to the co-expression attenuation of genes inside the locus during carcinogenesis. We further analyzed the 3D DNA interaction profile by the publicly accessible Hi-C database. Consistently, the HOXA locus in normal cell lines compromised isolated topological domains while merging to the domain nearby in cancer cell lines. In conclusion, the dysregulation of the HOXA locus provides a novel insight into pan-cancer carcinogenesis.


Author(s):  
Stefano Franzini ◽  
Marco Di Stefano ◽  
Cristian Micheletti

Abstract Motivation Hi-C matrices are cornerstones for qualitative and quantitative studies of genome folding, from its territorial organization to compartments and topological domains. The high dynamic range of genomic distances probed in Hi-C assays reflects in an inherent stochastic background of the interactions matrices, which inevitably convolve the features of interest with largely non-specific ones. Results Here, we introduce and discuss essHi-C, a method to isolate the specific or essential component of Hi-C matrices from the non-specific portion of the spectrum compatible with random matrices. Systematic comparisons show that essHi-C improves the clarity of the interaction patterns, enhances the robustness against sequencing depth of topologically associating domains identification, allows the unsupervised clustering of experiments in different cell lines and recovers the cell-cycle phasing of single-cells based on Hi-C data. Thus, essHi-C provides means for isolating significant biological and physical features from Hi-C matrices. Availability and implementation The essHi-C software package is available at https://github.com/stefanofranzini/essHIC. Supplementary information Supplementary data are available at Bioinformatics online.


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