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1
Warfield, Linda, Jie Luo, Jeffrey Ranish, and Steven Hahn. "Function of Conserved Topological Regions within the Saccharomyces cerevisiae Basal Transcription Factor TFIIH." Molecular and Cellular Biology 36, no. 19 (July 5, 2016): 2464–75. http://dx.doi.org/10.1128/mcb.00182-16.
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TFIIH is a 10-subunit RNA polymerase II basal transcription factor with a dual role in DNA repair. TFIIH contains three enzymatic functions and over 30 conserved subdomains and topological regions. We systematically tested the function of these regions in three TFIIH core module subunits, i.e., Ssl1, Tfb4, and Tfb2, in the DNA translocase subunit Ssl2, and in the kinase module subunit Tfb3. Our results are consistent with previously predicted roles for the Tfb2 Hub, Ssl2 Lock, and Tfb3 Latch regions, with mutations in these elements typically having severe defects in TFIIH subunit association. We also found unexpected roles for other domains whose function had not previously been defined. First, the Ssl1-Tfb4 Ring domains are important for TFIIH assembly. Second, the Tfb2 Hub and HEAT domains have an unexpected role in association with Tfb3. Third, the Tfb3 Ring domain is important for association with many other TFIIH subunits. Fourth, a partial deletion of the Ssl1 N-terminal extension (NTE) domain inhibits TFIIH function without affecting subunit association. Finally, we used site-specific cross-linking to localize the Tfb3-binding surface on the Rad3 Arch domain. Our cross-linking results suggest that Tfb3 and Rad3 have an unusual interface, with Tfb3 binding on two opposite faces of the Arch.
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Marinov, Georgi K., Alexandro E. Trevino, Tingting Xiang, Anshul Kundaje, Arthur R. Grossman, and William J. Greenleaf. "Transcription-dependent domain-scale three-dimensional genome organization in the dinoflagellate Breviolum minutum." Nature Genetics 53, no. 5 (April 29, 2021): 613–17. http://dx.doi.org/10.1038/s41588-021-00848-5.
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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.
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Liu, Qian, Nelly Pante, Tom Misteli, Mohamed Elsagga, Melissa Crisp, Didier Hodzic, Brian Burke, and Kyle J. Roux. "Functional association of Sun1 with nuclear pore complexes." Journal of Cell Biology 178, no. 5 (August 27, 2007): 785–98. http://dx.doi.org/10.1083/jcb.200704108.
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Sun1 and 2 are A-type lamin-binding proteins that, in association with nesprins, form a link between the inner nuclear membranes (INMs) and outer nuclear membranes of mammalian nuclear envelopes. Both immunofluorescence and immunoelectron microscopy reveal that Sun1 but not Sun2 is intimately associated with nuclear pore complexes (NPCs). Topological analyses indicate that Sun1 is a type II integral protein of the INM. Localization of Sun1 to the INM is defined by at least two discrete regions within its nucleoplasmic domain. However, association with NPCs is dependent on the synergy of both nucleoplasmic and lumenal domains. Cells that are either depleted of Sun1 by RNA interference or that overexpress dominant-negative Sun1 fragments exhibit clustering of NPCs. The implication is that Sun1 represents an important determinant of NPC distribution across the nuclear surface.
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Willemin, Andréa, Lucille Lopez-Delisle, Christopher Chase Bolt, Marie-Laure Gadolini, Denis Duboule, and Eddie Rodriguez-Carballo. "Induction of a chromatin boundary in vivo upon insertion of a TAD border." PLOS Genetics 17, no. 7 (July 22, 2021): e1009691. http://dx.doi.org/10.1371/journal.pgen.1009691.
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Mammalian genomes are partitioned into sub-megabase to megabase-sized units of preferential interactions called topologically associating domains or TADs, which are likely important for the proper implementation of gene regulatory processes. These domains provide structural scaffolds for distant cis regulatory elements to interact with their target genes within the three-dimensional nuclear space and architectural proteins such as CTCF as well as the cohesin complex participate in the formation of the boundaries between them. However, the importance of the genomic context in providing a given DNA sequence the capacity to act as a boundary element remains to be fully investigated. To address this question, we randomly relocated a topological boundary functionally associated with the mouse HoxD gene cluster and show that it can indeed act similarly outside its initial genomic context. In particular, the relocated DNA segment recruited the required architectural proteins and induced a significant depletion of contacts between genomic regions located across the integration site. The host chromatin landscape was re-organized, with the splitting of the TAD wherein the boundary had integrated. These results provide evidence that topological boundaries can function independently of their site of origin, under physiological conditions during mouse development.
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Zhan, Y., L. Giorgetti, and G. Tiana. "Modelling genome-wide topological associating domains in mouse embryonic stem cells." Chromosome Research 25, no. 1 (January 20, 2017): 5–14. http://dx.doi.org/10.1007/s10577-016-9544-6.
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Zhang, Guangzhi, and Hélène Sanfaçon. "Characterization of Membrane Association Domains within the Tomato Ringspot Nepovirus X2 Protein, an Endoplasmic Reticulum-Targeted Polytopic MembraneProtein." Journal of Virology 80, no. 21 (August 23, 2006): 10847–57. http://dx.doi.org/10.1128/jvi.00789-06.
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ABSTRACT Replication of nepoviruses (family Comoviridae) occurs in association with endoplasmic reticulum (ER)-derived membranes. We have previously shown that the putative nucleoside triphosphate-binding protein (NTB) of Tomato ringspot nepovirus is an integral membrane protein with two ER-targeting sequences and have suggested that it anchors the viral replication complex (VRC) to the membranes. A second highly hydrophobic protein domain (X2) is located immediately upstream of the NTB domain in the RNA1-encoded polyprotein. X2 shares conserved sequence motifs with the comovirus 32-kDa protein, an ER-targeted protein implicated in VRC assembly. In this study, we examined the ability of X2 to associate with intracellular membranes. The X2 protein was fused to the green fluorescent protein and expressed in Nicotiana benthamiana by agroinfiltration. Confocal microscopy and membrane flotation experiments suggested that X2 is targeted to ER membranes. Mutagenesis studies revealed that X2 contains multiple ER-targeting domains, including two C-terminal transmembrane helices and a less-well-defined domain further upstream. To investigate the topology of the protein in the membrane, in vitro glycosylation assays were conducted using X2 derivatives that contained N-glycosylation sites introduced at the N or C termini of the protein. The results led us to propose a topological model for X2 in which the protein traverses the membrane three times, with the N terminus oriented in the lumen and the C terminus exposed to the cytoplasmic face. Taken together, our results indicate that X2 is an ER-targeted polytopic membrane protein and raises the possibility that it acts as a second membrane anchor for the VRC.
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Davidson, Iain F., Benedikt Bauer, Daniela Goetz, Wen Tang, Gordana Wutz, and Jan-Michael Peters. "DNA loop extrusion by human cohesin." Science 366, no. 6471 (November 21, 2019): 1338–45. http://dx.doi.org/10.1126/science.aaz3418.
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Eukaryotic genomes are folded into loops and topologically associating domains, which contribute to chromatin structure, gene regulation, and gene recombination. These structures depend on cohesin, a ring-shaped DNA-entrapping adenosine triphosphatase (ATPase) complex that has been proposed to form loops by extrusion. Such an activity has been observed for condensin, which forms loops in mitosis, but not for cohesin. Using biochemical reconstitution, we found that single human cohesin complexes form DNA loops symmetrically at rates up to 2.1 kilo–base pairs per second. Loop formation and maintenance depend on cohesin’s ATPase activity and on NIPBL-MAU2, but not on topological entrapment of DNA by cohesin. During loop formation, cohesin and NIPBL-MAU2 reside at the base of loops, which indicates that they generate loops by extrusion. Our results show that cohesin and NIPBL-MAU2 form an active holoenzyme that interacts with DNA either pseudo-topologically or non-topologically to extrude genomic interphase DNA into loops.
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Li, Yufang, Aoshen Wu, Gang Liu, and Lei Liu. "A Review of Methods to Quantify the Genomic Similarity of Topological Associating Domains." Journal of Computational Biology 26, no. 11 (November 1, 2019): 1326–38. http://dx.doi.org/10.1089/cmb.2019.0129.
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Franzini, Stefano, Marco Di Stefano, and Cristian Micheletti. "essHi-C: essential component analysis of Hi-C matrices." Bioinformatics 37, no. 15 (February 1, 2021): 2088–94. http://dx.doi.org/10.1093/bioinformatics/btab062.
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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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Soler-Vila, Paula, Pol Cuscó, Irene Farabella, Marco Di Stefano, and Marc A. Marti-Renom. "Hierarchical chromatin organization detected by TADpole." Nucleic Acids Research 48, no. 7 (February 21, 2020): e39-e39. http://dx.doi.org/10.1093/nar/gkaa087.
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Abstract The rapid development of Chromosome Conformation Capture (3C-based techniques), as well as imaging together with bioinformatics analyses, has been fundamental for unveiling that chromosomes are organized into the so-called topologically associating domains or TADs. While TADs appear as nested patterns in the 3C-based interaction matrices, the vast majority of available TAD callers are based on the hypothesis that TADs are individual and unrelated chromatin structures. Here we introduce TADpole, a computational tool designed to identify and analyze the entire hierarchy of TADs in intra-chromosomal interaction matrices. TADpole combines principal component analysis and constrained hierarchical clustering to provide a set of significant hierarchical chromatin levels in a genomic region of interest. TADpole is robust to data resolution, normalization strategy and sequencing depth. Domain borders defined by TADpole are enriched in main architectural proteins (CTCF and cohesin complex subunits) and in the histone mark H3K4me3, while their domain bodies, depending on their activation-state, are enriched in either H3K36me3 or H3K27me3, highlighting that TADpole is able to distinguish functional TAD units. Additionally, we demonstrate that TADpole's hierarchical annotation, together with the new DiffT score, allows for detecting significant topological differences on Capture Hi-C maps between wild-type and genetically engineered mouse.
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Gómez-Marín, Carlos, Juan J. Tena, Rafael D. Acemel, Macarena López-Mayorga, Silvia Naranjo, Elisa de la Calle-Mustienes, Ignacio Maeso, et al. "Evolutionary comparison reveals that diverging CTCF sites are signatures of ancestral topological associating domains borders." Proceedings of the National Academy of Sciences 112, no. 24 (June 1, 2015): 7542–47. http://dx.doi.org/10.1073/pnas.1505463112.
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Increasing evidence in the last years indicates that the vast amount of regulatory information contained in mammalian genomes is organized in precise 3D chromatin structures. However, the impact of this spatial chromatin organization on gene expression and its degree of evolutionary conservation is still poorly understood. The Six homeobox genes are essential developmental regulators organized in gene clusters conserved during evolution. Here, we reveal that the Six clusters share a deeply evolutionarily conserved 3D chromatin organization that predates the Cambrian explosion. This chromatin architecture generates two largely independent regulatory landscapes (RLs) contained in two adjacent topological associating domains (TADs). By disrupting the conserved TAD border in one of the zebrafish Six clusters, we demonstrate that this border is critical for preventing competition between promoters and enhancers located in separated RLs, thereby generating different expression patterns in genes located in close genomic proximity. Moreover, evolutionary comparison of Six-associated TAD borders reveals the presence of CCCTC-binding factor (CTCF) sites with diverging orientations in all studied deuterostomes. Genome-wide examination of mammalian HiC data reveals that this conserved CTCF configuration is a general signature of TAD borders, underscoring that common organizational principles underlie TAD compartmentalization in deuterostome evolution.
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Shah, Maryam, Arsalan Riaz, and Faisal Khan. "Abstract 6338: Higher-resolution protein interaction networks for precision medicine: A case for drug repurposing in head and neck cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6338. http://dx.doi.org/10.1158/1538-7445.am2022-6338.
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Abstract Protein-Protein Interaction (PPI) networks can be useful scaffolds for the integration of whole cell multi-omics datasets that can aid significantly in drug discovery research. This study aims to use domain-domain interaction (DDI) data to produce high resolution protein interaction networks with enhanced topological insights for head and neck squamous cell carcinoma as well as the more well studies, triple negative breast cancer (TNBC). An extensive literature review identified 65 driver genes for HNSCC and 19 genes for TNBC which collectively had 557 and 316 protein domains. Eventually, 343/557 and 191/316 domains had well-annotated somatic mutations reported in COSMIC. PPI networks were created using BioGrid and STRING data and the top two hubs in PPI networks were TP53 for HNSCC and EGFR for TNBC, while the top two hubs in DDI networks were PF12796 (NOTCH) and PF07714 (EGFR) for HNSCC and TNBC networks, respectively. The top nodes in the densest sub-clusters based on module analysis in PPI networks were ERBB4, MET and NOTCH1 for HNSCC, and FGFR1, AR, and EGFR for TNBC. For DDI networks, the top nodes in the densest subcluster for HNSCC were PF06816 (NOTCH1-3), while for TNBC PF07714 domains from FGFR1, ERBB2 and EGFR were the top nodes. Our preliminary results re-emphasize the significance of NOTCH, EGFR and TP53, and their domains, in cancer networks. Next, we attempted to decipher potential candidates for drug repurposing and were able to map 20 out of the 31 FDA approved cancer drugs against proteins within our HNSCC network. EGFR was revealed as a hub gene in both HNSCC and TNBC networks with most of the therapies designed against the PF07714 kinase domain of EGFR. PF07714 is also a common domain in ERBB4, EPHA2, MAP2K1 and MET, and was targeted by different drugs in other cancer types. Next, we attempt to undertake an in vitro drug screen of all candidates against HNSCC cell lines to validate our in silico findings. Citation Format: Maryam Shah, Arsalan Riaz, Faisal Khan. Higher-resolution protein interaction networks for precision medicine: A case for drug repurposing in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6338.
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Bournonville, Clément, Hilde Hénon, Thibaut Dondaine, Christine Delmaire, Stephanie Bombois, Anne-Marie Mendyk, Charlotte Cordonnier, et al. "Identification of a specific functional network altered in poststroke cognitive impairment." Neurology 90, no. 21 (April 20, 2018): e1879-e1888. http://dx.doi.org/10.1212/wnl.0000000000005553.
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ObjectiveTo study the association between poststroke cognitive impairment and defining a specific resting functional marker.MethodsThe resting-state functional connectivity 6 months after an ischemic stroke in 56 patients was investigated. Twenty-nine of the patients who had an impairment of one or several cognitive domains were compared to 27 without any cognitive deficit. We studied the whole-brain connectivity using 2 complementary approaches: graph theory to study the functional network organization and network-based statistics to explore connectivity between brain regions. We assessed the potential cortical atrophy using voxel-based morphometry analysis.ResultsThe overall topological organization of the functional network was not altered in cognitively impaired stroke patients, who had the same mean node degree, average clustering coefficient, and global efficiency as cognitively healthy stroke patients. Network-based statistics analysis showed that poststroke cognitive impairment was associated with dysfunction of a whole-brain network composed of 167 regions and 178 connections, and functional disconnections between superior, middle, and inferior frontal gyri and the superior and inferior temporal gyri. These regions had connections that were specifically and positively correlated with cognitive domain scores. No intergroup differences in overall gray matter thickness and ischemic infarct topography were observed. To assess the effect of prestroke white matter hyperintensities on connectivity, we included the initial Fazekas scale in the regression model for a second network-based analysis. The resulting network was associated with the same key alterations but had fewer connections.ConclusionsThe observed functional network alterations suggest that the appearance of a cognitive impairment following stroke may be associated with a particular functional alteration, shared specifically between cognitive domains.
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Depierre, David, Charlène Perrois, Naomi Schickele, Priscillia Lhoumaud, Mahdia Abdi-Galab, Olivier Fosseprez, Alexandre Heurteau, Raphaël Margueron, and Olivier Cuvier. "Chromatin in 3D distinguishes dMes-4/NSD and Hypb/dSet2 in protecting genes from H3K27me3 silencing." Life Science Alliance 6, no. 11 (September 8, 2023): e202302038. http://dx.doi.org/10.26508/lsa.202302038.
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Cell type-specific barcoding of genomes requires the establishment of hundreds of heterochromatin domains where heterochromatin-associated repressive complexes hinder chromatin accessibility thereby silencing genes. At heterochromatin–euchromatin borders, regulation of accessibility not only depends on the delimitation of heterochromatin but may also involve interplays with nearby genes and their transcriptional activity, or alternatively on histone modifiers, chromatin barrier insulators, and more global demarcation of chromosomes into 3D compartmentalized domains and topological-associating domain (TADs). Here, we show that depletion of H3K36 di- or tri-methyl histone methyltransferases dMes-4/NSD or Hypb/dSet2 induces reproducible increasing levels of H3K27me3 at heterochromatin borders including in nearby promoters, thereby repressing hundreds of genes. Furthermore, dMes-4/NSD influences genes demarcated by insulators and TAD borders, within chromatin hubs, unlike transcription-coupled action of Hypb/dSet2 that protects genes independently of TADs. Insulator mutants recapitulate the increase of H3K27me3 upon dMes-4/NSD depletion unlike Hypb/dSet2. Hi-C data demonstrate how dMes-4/NSD blocks propagation of long-range interactions onto active regions. Our data highlight distinct mechanisms protecting genes from H3K27me3 silencing, highlighting a direct influence of H3K36me on repressive TADs.
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Vidal, Miguel. "Polycomb Assemblies Multitask to Regulate Transcription." Epigenomes 3, no. 2 (June 20, 2019): 12. http://dx.doi.org/10.3390/epigenomes3020012.
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The Polycomb system is made of an evolutionary ancient group of proteins, present throughout plants and animals. Known initially from developmental studies with the fly Drosophila melanogaster, they were associated with stable sustainment of gene repression and maintenance of cell identity. Acting as multiprotein assemblies with an ability to modify chromatin, through chemical additions to histones and organization of topological domains, they have been involved subsequently in control of developmental transitions and in cell homeostasis. Recent work has unveiled an association of Polycomb components with transcriptionally active loci and the promotion of gene expression, in clear contrast with conventional recognition as repressors. Focusing on mammalian models, I review here advances concerning roles in transcriptional control. Among new findings highlighted is the regulation of their catalytic properties, recruiting to targets, and activities in chromatin organization and compartmentalization. The need for a more integrated approach to the study of the Polycomb system, given its fundamental complexity and its adaptation to cell context, is discussed.
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Coetzee, Gerhard A. "Understanding Non-Mendelian Genetic Risk." Current Genomics 20, no. 5 (December 3, 2019): 322–24. http://dx.doi.org/10.2174/1389202920666191018085511.
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This opinion paper highlights strategies for a better understanding of non-Mendelian genetic risk that was revealed by genome-wide association studies (GWAS) of complex diseases. The genetic risk resides predominantly in non-coding regulatory DNA, such as in enhancers. The identification of mechanisms, the causal variants (mainly SNPs), and their target genes are, however, not always apparent but are likely involved in a network of risk determinants; the identification presents a bottle-neck in the full understanding of the genetics of complex phenotypes. Here, we propose strategies to identify functional SNPs and link risk enhancers with their target genes. The strategies are 1) identifying finemapped SNPs that break/form response elements within chromatin bio-features in relevant cell types 2) considering the nearest gene on linear DNA, 3) analyzing eQTLs, 4) mapping differential DNA methylation regions and relating them to gene expression, 5) employing genomic editing with CRISPR/cas9 and 6) identifying topological associated chromatin domains using chromatin conformation capture.
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Wu, Ziyan, Meng Cao, Xin Di, Kai Wu, Yu Gao, and Xiaobo Li. "Regional Topological Aberrances of White Matter- and Gray Matter-Based Functional Networks for Attention Processing May Foster Traumatic Brain Injury-Related Attention Deficits in Adults." Brain Sciences 12, no. 1 (December 24, 2021): 16. http://dx.doi.org/10.3390/brainsci12010016.
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Traumatic brain injury (TBI) is highly prevalent in adults. TBI-related functional brain alterations have been linked with common post-TBI neurobehavioral sequelae, with unknown neural substrates. This study examined the systems-level functional brain alterations in white matter (WM) and gray matter (GM) for visual sustained-attention processing, and their interactions and contributions to post-TBI attention deficits. Task-based functional MRI data were collected from 42 adults with TBI and 43 group-matched normal controls (NCs), and analyzed using the graph theoretic technique. Global and nodal topological properties were calculated and compared between the two groups. Correlation analyses were conducted between the neuroimaging measures that showed significant between-group differences and the behavioral symptom measures in attention domain in the groups of TBI and NCs, respectively. Significantly altered nodal efficiencies and/or degrees in several WM and GM nodes were reported in the TBI group, including the posterior corona radiata (PCR), posterior thalamic radiation (PTR), postcentral gyrus (PoG), and superior temporal sulcus (STS). Subjects with TBI also demonstrated abnormal systems-level functional synchronization between the PTR and STS in the right hemisphere, hypo-interaction between the PCR and PoG in the left hemisphere, as well as the involvement of systems-level functional aberrances in the PCR in TBI-related behavioral impairments in the attention domain. The findings of the current study suggest that TBI-related systems-level functional alterations associated with these two major-association WM tracts, and their anatomically connected GM regions may play critical role in TBI-related behavioral deficits in attention domains.
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Goudarzi, Shervin, Meghana Pagadala, Adam Klie, James V. Talwar, and Hannah Carter. "Epigenetic germline variants predict cancer prognosis and risk and distribute uniquely in topologically associating domains." F1000Research 12 (September 1, 2023): 1083. http://dx.doi.org/10.12688/f1000research.139476.1.
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Background: Methylation quantitative trait loci (meQTLs) associate with different levels of local DNA methylation in cancers. Here, we investigated whether the distribution of cancer meQTLs reflected functional organization of the genome in the form of chromatin topologically associated domains (TADs) and evaluated whether cancer meQTLs near known driver genes have the potential to influence cancer risk or progression. Methods: Published cancer meQTLs were analyzed according to their location in transcriptionally active or inactive TADs and TAD boundary regions. Cancer meQTLs near known cancer genes were analyzed for association with cancer risk in the UKBioBank and prognosis in The Cancer Genome Atlas (TCGA). Results: In TAD boundary regions, the density of cancer meQTLs was higher near inactive TADs. Furthermore, we observed an enrichment of cancer meQTLs in active TADs near tumor suppressors, whereas there was a depletion of such meQTLs near oncogenes. Several meQTLs were associated with cancer risk in the UKBioBank, and we were able to reproduce breast cancer risk associations in the DRIVE cohort. Survival analysis in TCGA implicated a number of meQTLs in 13 tumor types. In 10 of these, polygenic cancer meQTL scores were associated with increased hazard in a CoxPH analysis. Risk and survival-associated meQTLs tended to affect cancer genes involved in DNA damage repair and cellular adhesion and reproduced cancer-specific associations reported in prior literature. Conclusions: This study provides evidence that genetic variants that influence local DNA methylation are affected by chromatin structure and can impact tumor evolution.
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Roversi, Pietro, Lucia Marti, Alessandro T. Caputo, Dominic S. Alonzi, Johan C. Hill, Kyle C. Dent, Abhinav Kumar, et al. "Interdomain conformational flexibility underpins the activity of UGGT, the eukaryotic glycoprotein secretion checkpoint." Proceedings of the National Academy of Sciences 114, no. 32 (July 24, 2017): 8544–49. http://dx.doi.org/10.1073/pnas.1703682114.
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Glycoproteins traversing the eukaryotic secretory pathway begin life in the endoplasmic reticulum (ER), where their folding is surveyed by the 170-kDa UDP-glucose:glycoprotein glucosyltransferase (UGGT). The enzyme acts as the single glycoprotein folding quality control checkpoint: it selectively reglucosylates misfolded glycoproteins, promotes their association with ER lectins and associated chaperones, and prevents premature secretion from the ER. UGGT has long resisted structural determination and sequence-based domain boundary prediction. Questions remain on how this single enzyme can flag misfolded glycoproteins of different sizes and shapes for ER retention and how it can span variable distances between the site of misfold and a glucose-accepting N-linked glycan on the same glycoprotein. Here, crystal structures of a full-length eukaryotic UGGT reveal four thioredoxin-like (TRXL) domains arranged in a long arc that terminates in two β-sandwiches tightly clasping the glucosyltransferase domain. The fold of the molecule is topologically complex, with the first β-sandwich and the fourth TRXL domain being encoded by nonconsecutive stretches of sequence. In addition to the crystal structures, a 15-Å cryo-EM reconstruction reveals interdomain flexibility of the TRXL domains. Double cysteine point mutants that engineer extra interdomain disulfide bridges rigidify the UGGT structure and exhibit impaired activity. The intrinsic flexibility of the TRXL domains of UGGT may therefore endow the enzyme with the promiscuity needed to recognize and reglucosylate its many different substrates and/or enable reglucosylation of N-linked glycans situated at variable distances from the site of misfold.
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Chakrabarty, Broto, and Nita Parekh. "Sequence and Structure-Based Analyses of Human Ankyrin Repeats." Molecules 27, no. 2 (January 10, 2022): 423. http://dx.doi.org/10.3390/molecules27020423.
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Ankyrin is one of the most abundant protein repeat families found across all forms of life. It is found in a variety of multi-domain and single domain proteins in humans with diverse number of repeating units. They are observed to occur in several functionally diverse proteins, such as transcriptional initiators, cell cycle regulators, cytoskeletal organizers, ion transporters, signal transducers, developmental regulators, and toxins, and, consequently, defects in ankyrin repeat proteins have been associated with a number of human diseases. In this study, we have classified the human ankyrin proteins into clusters based on the sequence similarity in their ankyrin repeat domains. We analyzed the amino acid compositional bias and consensus ankyrin motif sequence of the clusters to understand the diversity of the human ankyrin proteins. We carried out network-based structural analysis of human ankyrin proteins across different clusters and showed the association of conserved residues with topologically important residues identified by network centrality measures. The analysis of conserved and structurally important residues helps in understanding their role in structural stability and function of these proteins. In this paper, we also discuss the significance of these conserved residues in disease association across the human ankyrin protein clusters.
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Mei, Shufang, Juntao Ke, Jianbo Tian, Pingting Ying, Nan Yang, Xiaoyang Wang, Danyi Zou, et al. "A functional variant in the boundary of a topological association domain is associated with pancreatic cancer risk." Molecular Carcinogenesis 58, no. 10 (June 24, 2019): 1855–62. http://dx.doi.org/10.1002/mc.23077.
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Simmons, James R., Ran An, Bright Amankwaa, Shannon Zayac, Justin Kemp, and Mariano Labrador. "Phosphorylated histone variant γH2Av is associated with chromatin insulators in Drosophila." PLOS Genetics 18, no. 10 (October 5, 2022): e1010396. http://dx.doi.org/10.1371/journal.pgen.1010396.
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Chromatin insulators are responsible for orchestrating long-range interactions between enhancers and promoters throughout the genome and align with the boundaries of Topologically Associating Domains (TADs). Here, we demonstrate an association between gypsy insulator proteins and the phosphorylated histone variant H2Av (γH2Av), normally a marker of DNA double strand breaks. Gypsy insulator components colocalize with γH2Av throughout the genome, in polytene chromosomes and in diploid cells in which Chromatin IP data shows it is enriched at TAD boundaries. Mutation of insulator components su(Hw) and Cp190 results in a significant reduction in γH2Av levels in chromatin and phosphatase inhibition strengthens the association between insulator components and γH2Av and rescues γH2Av localization in insulator mutants. We also show that γH2Av, but not H2Av, is a component of insulator bodies, which are protein condensates that form during osmotic stress. Phosphatase activity is required for insulator body dissolution after stress recovery. Together, our results implicate the H2A variant with a novel mechanism of insulator function and boundary formation.
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Malkin, A. J., A. McPherson, and P. D. Gershon. "Structure of Intracellular Mature Vaccinia Virus Visualized by In Situ Atomic Force Microscopy." Journal of Virology 77, no. 11 (June 1, 2003): 6332–40. http://dx.doi.org/10.1128/jvi.77.11.6332-6340.2003.
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ABSTRACT Vaccinia virus, the basis of the smallpox vaccine, is one of the largest viruses to replicate in humans. We have used in situ atomic force microscopy (AFM) to directly visualize fully hydrated, intact intracellular mature vaccinia virus (IMV) virions and chemical and enzymatic treatment products thereof. The latter included virion cores, core-enveloping coats, and core substructures. The isolated coats appeared to be composed of a highly cross-linked protein array. AFM imaging of core substructures indicated association of the linear viral DNA genome with a segmented protein sheath forming an extended ∼16-nm-diameter filament with helical surface topography; enclosure of this filament within a 30- to 40-nm-diameter tubule which also shows helical topography; and enclosure of the folded, condensed 30- to 40-nm-diameter tubule within the core by a wall covered with peg-like projections. Proteins observed attached to the 30- to 40-nm-diameter tubules may mediate folding and/or compaction of the tubules and/or represent vestiges of the core wall and/or pegs. An accessory “satellite domain” was observed protruding from the intact core. This corresponded in size to isolated 70- to 100-nm-diameter particles that were imaged independently and might represent detached accessory domains. AFM imaging of intact virions indicated that IMV underwent a reversible shrinkage upon dehydration (as much as 2.2- to 2.5-fold in the height dimension), accompanied by topological and topographical changes, including protrusion of the satellite domain. As shown here, the chemical and enzymatic dissection of large, asymmetrical virus particles in combination with in situ AFM provides an informative complement to other structure determination techniques.
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Zhao, Lingyu, Chuhong He, and Xiaorong Zhu. "A Fault Diagnosis Method for 5G Cellular Networks Based on Knowledge and Data Fusion." Sensors 24, no. 2 (January 9, 2024): 401. http://dx.doi.org/10.3390/s24020401.
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As 5G networks become more complex and heterogeneous, the difficulty of network operation and maintenance forces mobile operators to find new strategies to stay competitive. However, most existing network fault diagnosis methods rely on manual testing and time stacking, which suffer from long optimization cycles and high resource consumption. Therefore, we herein propose a knowledge- and data-fusion-based fault diagnosis algorithm for 5G cellular networks from the perspective of big data and artificial intelligence. The algorithm uses a generative adversarial network (GAN) to expand the data set collected from real network scenarios to balance the number of samples under different network fault categories. In the process of fault diagnosis, a naive Bayesian model (NBM) combined with domain expert knowledge is firstly used to pre-diagnose the expanded data set and generate a topological association graph between the data with solid engineering significance and interpretability. Then, as the pre-diagnostic prior knowledge, the topological association graph is fed into the graph convolutional neural network (GCN) model simultaneously with the training data set for model training. We use a data set collected by Minimization of Drive Tests under real network scenarios in Lu’an City, Anhui Province, in August 2019. The simulation results demonstrate that the algorithm outperforms other traditional models in fault detection and diagnosis tasks, achieving an accuracy of 90.56% and a macro F1 score of 88.41%.
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Pandey, Karran, Joy Merwin Monteiro, and Vijay Natarajan. "An Integrated Geometric and Topological Approach for the Identification and Visual Analysis of Rossby Wave Packets." Monthly Weather Review 148, no. 8 (July 9, 2020): 3139–55. http://dx.doi.org/10.1175/mwr-d-20-0014.1.
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Abstract A new method for identifying Rossby wave packets (RWPs) using 6-hourly data from the ERA-Interim is presented. The method operates entirely in the spatial domain and relies on the geometric and topological properties of the meridional wind field to identify RWPs. The method represents RWPs as nodes and edges of a dual graph instead of the more common envelope representation. This novel representation allows access to both RWP phase and amplitude information. Local maxima and minima of the meridional wind field are collected into groups. Each group, called a υ-max cluster or υ-min cluster of the meridional wind field, represents a potential wave component. Nodes of the dual graph represent a υ-max cluster or υ-min cluster. Alternating υ-max clusters and υ-min clusters are linked by edges of the dual graph, called the RWP association graph. Amplitude and discrete gradient-based filtering applied on the association graph helps identify RWPs of interest. The method is inherently robust against noise and does not require smoothing of the input data. The main parameters that control the performance of the method and their impact on the identified RWPs are discussed. All filtering and RWP identification operations are performed on the association graph as opposed to directly on the wind field, leading to computational efficiency. Advantages and limitations of the method are discussed and are compared against (transform-based) envelope methods in a series of experiments.
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Papanicolaou, Natali, and Alessandro Bonetti. "The New Frontier of Functional Genomics: From Chromatin Architecture and Noncoding RNAs to Therapeutic Targets." SLAS DISCOVERY: Advancing the Science of Drug Discovery 25, no. 6 (June 2, 2020): 568–80. http://dx.doi.org/10.1177/2472555220926158.
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Common diseases are complex, multifactorial disorders whose pathogenesis is influenced by the interplay of genetic predisposition and environmental factors. Genome-wide association studies have interrogated genetic polymorphisms across genomes of individuals to test associations between genotype and susceptibility to specific disorders, providing insights into the genetic architecture of several complex disorders. However, genetic variants associated with the susceptibility to common diseases are often located in noncoding regions of the genome, such as tissue-specific enhancers or long noncoding RNAs, suggesting that regulatory elements might play a relevant role in human diseases. Enhancers are cis-regulatory genomic sequences that act in concert with promoters to regulate gene expression in a precise spatiotemporal manner. They can be located at a considerable distance from their cognate target promoters, increasing the difficulty of their identification. Genomes are organized in domains of chromatin folding, namely topologically associating domains (TADs). Identification of enhancer–promoter interactions within TADs has revealed principles of cell-type specificity across several organisms and tissues. The vast majority of mammalian genomes are pervasively transcribed, accounting for a previously unappreciated complexity of the noncoding RNA fraction. Particularly, long noncoding RNAs have emerged as key players for the establishment of chromatin architecture and regulation of gene expression. In this perspective, we describe the new advances in the fields of transcriptomics and genome organization, focusing on the role of noncoding genomic variants in the predisposition of common diseases. Finally, we propose a new framework for the identification of the next generation of pharmacological targets for common human diseases.
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Mishra, Bharat, Nilesh Kumar, and M. Shahid Mukhtar. "Systems Biology and Machine Learning in Plant–Pathogen Interactions." Molecular Plant-Microbe Interactions® 32, no. 1 (January 2019): 45–55. http://dx.doi.org/10.1094/mpmi-08-18-0221-fi.
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Systems biology is an inclusive approach to study the static and dynamic emergent properties on a global scale by integrating multiomics datasets to establish qualitative and quantitative associations among multiple biological components. With an abundance of improved high throughput -omics datasets, network-based analyses and machine learning technologies are playing a pivotal role in comprehensive understanding of biological systems. Network topological features reveal most important nodes within a network as well as prioritize significant molecular components for diverse biological networks, including coexpression, protein–protein interaction, and gene regulatory networks. Machine learning techniques provide enormous predictive power through specific feature extraction from biological data. Deep learning, a subtype of machine learning, has plausible future applications because a domain expert for feature extraction is not needed in this algorithm. Inspired by diverse domains of biology, we here review classic systems biology techniques applied in plant immunity thus far. We also discuss additional advanced approaches in both graph theory and machine learning, which may provide new insights for understanding plant–microbe interactions. Finally, we propose a hybrid approach in plant immune systems that harnesses the power of both network biology and machine learning, with a potential to be applicable to both model systems and agronomically important crop plants.
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Jasnovidova, Olga, Tomas Klumpler, Karel Kubicek, Sergei Kalynych, Pavel Plevka, and Richard Stefl. "Structure and dynamics of the RNAPII CTDsome with Rtt103." Proceedings of the National Academy of Sciences 114, no. 42 (October 4, 2017): 11133–38. http://dx.doi.org/10.1073/pnas.1712450114.
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RNA polymerase II contains a long C-terminal domain (CTD) that regulates interactions at the site of transcription. The CTD architecture remains poorly understood due to its low sequence complexity, dynamic phosphorylation patterns, and structural variability. We used integrative structural biology to visualize the architecture of the CTD in complex with Rtt103, a 3′-end RNA-processing and transcription termination factor. Rtt103 forms homodimers via its long coiled-coil domain and associates densely on the repetitive sequence of the phosphorylated CTD via its N-terminal CTD-interacting domain. The CTD–Rtt103 association opens the compact random coil structure of the CTD, leading to a beads-on-a-string topology in which the long rod-shaped Rtt103 dimers define the topological and mobility restraints of the entire assembly. These findings underpin the importance of the structural plasticity of the CTD, which is templated by a particular set of CTD-binding proteins.
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Wang, Daifeng, Shuang Liu, Jonathan Warrell, Hyejung Won, Xu Shi, Fabio C. P. Navarro, Declan Clarke, et al. "Comprehensive functional genomic resource and integrative model for the human brain." Science 362, no. 6420 (December 13, 2018): eaat8464. http://dx.doi.org/10.1126/science.aat8464.
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Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.
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Ding, Shilei, Halima Medjahed, Jérémie Prévost, Mathieu Coutu, Shi-Hua Xiang, and Andrés Finzi. "Lineage-Specific Differences between the gp120 Inner Domain Layer 3 of Human Immunodeficiency Virus and That of Simian Immunodeficiency Virus." Journal of Virology 90, no. 22 (August 17, 2016): 10065–73. http://dx.doi.org/10.1128/jvi.01215-16.
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ABSTRACT Binding of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) gp120 exterior envelope glycoprotein to CD4 triggers conformational changes in gp120 that promote its interaction with one of the chemokine receptors, usually CCR5, ultimately leading to gp41-mediated virus-cell membrane fusion and entry. We previously described that topological layers (layer 1, layer 2, and layer 3) in the gp120 inner domain contribute to gp120-trimer association in the unliganded state but also help secure CD4 binding. Relative to layer 1 of HIV-1 gp120, the SIVmac239 gp120 layer 1 plays a more prominent role in maintaining gp120-trimer association but is minimally involved in promoting CD4 binding, which could be explained by the existence of a well-conserved tryptophan at position 375 (Trp 375) in HIV-2/SIVsmm. In this study, we investigated the role of SIV layer 3 in viral entry, cell-to-cell fusion, and CD4 binding. We observed that a network of interactions involving some residues of the β8-α5 region in SIVmac239 layer 3 may contribute to CD4 binding by helping shape the nearby Phe 43 cavity, which directly contacts CD4. In summary, our results suggest that layer 3 in SIV has a greater impact on CD4 binding than in HIV-1. This work defines lineage-specific differences in layer 3 from HIV-1 and that from SIV. IMPORTANCE CD4-induced conformational changes in the gp120 inner domain involve rearrangements between three topological layers. While the role of layers 1 to 3 for HIV-1 and layers 1 and 2 for SIV on gp120 transition to the CD4-bound conformation has been reported, the role of SIV layer 3 remains unknown. Here we report that SIV layer 3 has a greater impact on CD4 binding than does layer 3 in HIV-1 gp120. This work defines lineage-specific differences in layer 3 from HIV-1 and SIV.
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Torchia, Jonathan, Mital Bhakta, Cory Padilla, Meredith L. Carpenter, Philip Uren, and Lisa Munding. "Abstract LB287: VariLink: A rapid, high-resolution proximity ligation method for the detection of structural variants and chromatin topology features in cancer." Cancer Research 84, no. 7_Supplement (April 5, 2024): LB287. http://dx.doi.org/10.1158/1538-7445.am2024-lb287.
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Abstract Despite numerous technological advances, including the widespread adoption of next-generation sequencing, many clinically relevant cancer driver mutations go undetected. The reason for this gap in understanding is two-fold: 1) Structural variants (SVs) are particularly challenging to detect using shotgun or long read-based approaches, particularly in heterogenous samples; and 2) It is increasingly accepted that epigenetic dysregulation may be a driver of disease state through mechanisms such as enhancer hijacking or changes to 3D genome organization. To address this gap in understanding, we developed VariLink: a dual-purpose proximity ligation library protocol that yields high-quality, high-resolution, unbiased Hi-C libraries capable of sensitive detection of structural variants and chromatin topological features from a single data set. Importantly, the VariLink protocol can be performed in under 8 hours—less than half of the time required for conventional Hi-C protocols. In the current study, we demonstrate the performance of VariLink for the detection of variants within the primary sequence (such as SVs, SNVs/Indels, and CNVs) in addition to high-resolution reporting of 3D chromatin conformation. We performed benchmarking analyses for both genetic variant detection and chromatin topology in two well-characterized lymphoblast cell lines (GM12878 and K562). We demonstrate the capability of VariLink data to detect interchromosomal translocations with 10-fold higher sensitivity over shotgun. Furthermore, using hybridization capture to detect the BCR-ABL1 fusion in K562 cells, we show that fewer than 100k read pairs is sufficient to detect this fusion with high confidence in VariLink libraries. We find that the shotgun-like, uniform coverage of VariLink data also enables detection of SNVs/Indels with improved sensitivity and precision over conventional Hi-C methods. Importantly, we demonstrate that VariLink libraries maintain topological features consistent with biologically relevant topologically-associated domains (TADs) and chromatin loops, providing insight into novel epigenetic cancer drivers. VariLink enables higher-resolution assessments of chromatin topology over conventional multi-RE-based Hi-C approaches, as demonstrated by 50% more TADs and loops called at 5-kb resolution. Taken together, our data demonstrate that VariLink is a next-generation Hi-C method that enables sensitive detection of clinically relevant structural variants and high-resolution chromatin topology in a single, rapid workflow. Citation Format: Jonathan Torchia, Mital Bhakta, Cory Padilla, Meredith L. Carpenter, Philip Uren, Lisa Munding. VariLink: A rapid, high-resolution proximity ligation method for the detection of structural variants and chromatin topology features in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB287.
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Grob, Stefan. "Three-dimensional chromosome organization in flowering plants." Briefings in Functional Genomics 19, no. 2 (March 2020): 83–91. http://dx.doi.org/10.1093/bfgp/elz024.
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Abstract Research on plant three-dimensional (3D) genome architecture made rapid progress over the past 5 years. Numerous Hi-C interaction data sets were generated in a wide range of plant species, allowing for a comprehensive overview on 3D chromosome folding principles in the plant kingdom. Plants lack important genes reported to be vital for chromosome folding in animals. However, similar 3D structures such as topologically associating domains and chromatin loops were identified. Recent studies in Arabidopsis thaliana revealed how chromosomal regions are positioned within the nucleus by determining their association with both, the nuclear periphery and the nucleolus. Additionally, many plant species exhibit high-frequency interactions among KNOT entangled elements, which are associated with safeguarding the genome from invasive DNA elements. Many of the recently published Hi-C data sets were generated to aid de novo genome assembly and remain to date little explored. These data sets represent a valuable resource for future comparative studies, which may lead to a more profound understanding of the evolution of 3D chromosome organization in plants.
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Tutino, Vincent M., Cathleen C. Kuo, Naval Avasthi, Hamid H. Rai, Muhammad Waqas, Adnan H. Siddiqui, James N. Jarvis, and Kerry E. Poppenberg. "Chromatin architecture around stroke haplotypes provides evidence that genetic risk is conferred through vascular cells." Epigenomics 14, no. 5 (March 2022): 243–59. http://dx.doi.org/10.2217/epi-2021-0307.
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Introduction: Genome-wide association studies (GWAS) have identified numerous stroke-associated SNPs. To understand how SNPs affect gene expression related to increased stroke risk, we studied epigenetic landscapes surrounding 26 common, validated stroke-associated loci. Methods: We mapped the SNPs to linkage disequilibrium (LD) blocks and examined H3K27ac, H3K4me1, H3K9ac, and H3K4me3 histone marks and transcription-factor binding-sites in pathologically relevant cell types (hematopoietic and vascular cells). Hi-C data were used to identify topologically associated domains (TADs) encompassing the LD blocks and overlapping genes. Results: Fibroblasts, smooth muscle, and endothelial cells showed significant enrichment for enhancer-associated marks within stroke-associated LD blocks. Genes within encompassing TADs reflected vessel homeostasis, cellular turnover, and enzymatic activity. Conclusions: Stroke-associated genetic variants confer risk predominantly through vascular cells rather than hematopoietic cell types.
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Soibam, Benjamin. "Association between Triplex-Forming Sites of Cardiac Long Noncoding RNA GATA6-AS1 and Chromatin Organization." Non-Coding RNA 8, no. 3 (June 1, 2022): 41. http://dx.doi.org/10.3390/ncrna8030041.
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This study explored the relationship between 3D genome organization and RNA–DNA triplex-forming sites of long noncoding RNAs (lncRNAs), a group of RNAs that do not code for proteins but are important factors regulating different aspects of genome activity. The triplex-forming sites of anti-sense cardiac lncRNA GATA6-AS1 derived from DBD-Capture-Seq were examined and compared to modular features of 3D genome organization called topologically associated domains (TADs) obtained from Hi-C data. It was found that GATA6-AS1 triplex-forming sites are positioned non-randomly in TADs and their boundaries. The triplex sites showed a preference for TAD boundaries over internal regions of TADs. Computational prediction analysis indicated that CTCF, the key protein involved in TAD specification, may interact with GATA6-AS1, and their binding sites correlate with each other. Examining locations of repeat elements in the genome suggests that the ability of lncRNA GATA6-AS1 to form triplex sites with many genomic locations may be achieved by the rapid expansion of different repeat elements. Some of the triplex-forming sites were found to be positioned in regions that undergo dynamic chromatin organization events such as loss/gain of TAD boundaries during cardiac differentiation. These observed associations suggest that lncRNA–DNA triplex formation may contribute to the specification of TADs in 3D genome organization.
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Lee, Hanjun, Ioanna-Maria Gkotinakou, Badri Krishnan, Nicholas J. Dyson, Michael S. Lawrence, and Ioannis Sanidas. "Abstract 1648: RB represses cohesin-dependent loop formation and activates E2F-independent transcription." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1648. http://dx.doi.org/10.1158/1538-7445.am2024-1648.
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Abstract The retinoblastoma protein (RB) suppresses the activity of the E2F transcription factor family, controlling cellular proliferation. Recent studies, however, indicate that RB's role in chromatin organization, which is not yet fully understood, might be distinct from this E2F-dependent regulation. Employing chromosome conformation capture at a single nucleosome resolution, we identified RB as a cell cycle-regulated repressor of cohesin-dependent loop formation at topologically associating domain (TAD) boundaries. RB depletion increased the number and size of cohesin-dependent loops and strengthened topologically associating domains (TADs). This phenomenon was specific to the G1 phase and was not observed in the S phase, indicating that this novel RB function is regulated by the cell cycle. Mechanistically, RB showed extensive colocalization with cohesin in the human genome, and it impacted cohesin’s distribution on the chromatin. Active RB reduced cohesin from RB-bound TAD boundaries and decreased cohesin activity therein, as assessed by the increased K105/106 acetylation of the cohesin subunit SMC3. This led to reduced insulation in chromosome conformation capture assays. Importantly, by weakening the insulation activity of the adjacent insulators, RB non-canonically enhanced the expression of non-E2F target genes salient for cell adhesion and extracellular matrix organization. When RB was lost, cells showed a more rapid cellular detachment rate and an elevated migration rate, indicating that this novel RB function controls specific transcriptional programs rather than arbitrary genes to regulate the process of cell adhesion and migration. Overall, we conclude that RB has a central role in the interplay between cell cycle and chromatin organization, by repressing the cohesin-dependent loop formation at TAD boundaries. This RB function safeguards E2F-independent transcriptional programs driven by active enhancers and helps maintain cellular adhesion to the extracellular matrix. Citation Format: Hanjun Lee, Ioanna-Maria Gkotinakou, Badri Krishnan, Nicholas J. Dyson, Michael S. Lawrence, Ioannis Sanidas. RB represses cohesin-dependent loop formation and activates E2F-independent transcription [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1648.
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Kirsanova, E., B. Heringstad, A. Lewandowska‐Sabat, and I. Olsaker. "Identification of candidate genes affecting chronic subclinical mastitis in Norwegian Red cattle: combining genome‐wide association study, topologically associated domains and pathway enrichment analysis." Animal Genetics 51, no. 1 (December 6, 2019): 22–31. http://dx.doi.org/10.1111/age.12886.
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Wang, Yi, Pavanjeet Kaur, Zhen-Yu J. Sun, Mostafa A. Elbahnasawy, Zahra Hayati, Zhi-Song Qiao, Nhat N. Bui, et al. "Topological analysis of the gp41 MPER on lipid bilayers relevant to the metastable HIV-1 envelope prefusion state." Proceedings of the National Academy of Sciences 116, no. 45 (October 17, 2019): 22556–66. http://dx.doi.org/10.1073/pnas.1912427116.
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The membrane proximal external region (MPER) of HIV-1 envelope glycoprotein (gp) 41 is an attractive vaccine target for elicitation of broadly neutralizing antibodies (bNAbs) by vaccination. However, current details regarding the quaternary structural organization of the MPER within the native prefusion trimer [(gp120/41)3] are elusive and even contradictory, hindering rational MPER immunogen design. To better understand the structural topology of the MPER on the lipid bilayer, the adjacent transmembrane domain (TMD) was appended (MPER-TMD) and studied. Membrane insertion of the MPER-TMD was sensitive both to the TMD sequence and cytoplasmic residues. Antigen binding of MPER-specific bNAbs, in particular 10E8 and DH511.2_K3, was significantly impacted by the presence of the TMD. Furthermore, MPER-TMD assembly into 10-nm diameter nanodiscs revealed a heterogeneous membrane array comprised largely of monomers and dimers, as enumerated by bNAb Fab binding using single-particle electron microscopy analysis, arguing against preferential trimeric association of native MPER and TMD protein segments. Moreover, introduction of isoleucine mutations in the C-terminal heptad repeat to induce an extended MPER α-helical bundle structure yielded an antigenicity profile of cell surface-arrayed Env variants inconsistent with that found in the native prefusion state. In line with these observations, electron paramagnetic resonance analysis suggested that 10E8 inhibits viral membrane fusion by lifting the MPER N-terminal region out of the viral membrane, mandating the exposure of residues that would be occluded by MPER trimerization. Collectively, our data suggest that the MPER is not a stable trimer, but rather a dynamic segment adapted for structural changes accompanying fusion.
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Capon, Daniel J., Nelson L. Chan, Larisa Troitskaya, Marina Fomin, Ursula Edman, Brendon Frank, Benjamin Z. Capon, et al. "Abstract 2730: Beyond antibodies and CAR-T: Topologically-engineered, super-dimeric antibody-like molecules with dual Fc domains for trispecific, bivalent targeting of CD19, CD20, and Fcgamma receptors." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2730. http://dx.doi.org/10.1158/1538-7445.am2024-2730.
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Abstract Background: Depletion of B cells has resulted in major therapeutic benefits in autoimmune diseases and hematological malignancies. Several FDA-approved B cell-depleting antibody-based therapies are available, including antibody-drug conjugates, T cell engagers, CAR-T cells, and antibody variants with enhanced effector functions through Fc engineering. However, a significant unmet need remains in both oncology and autoimmune disease. All currently approved B cell-depleting therapies target a single B cell antigen, increasing potential for incomplete depletion and emergence of escape mutants that give rise to relapse and treatment failure. Methods: Here we describe trispecific antibody-like molecules generated using GEM-DIMER technology. In addition to bivalent target binding of both CD19 and CD20, the GEM-DIMER candidates are designed to have two Fc domains to enable powerful effector functions via cooperative binding of Fcgamma receptors. The approach is based on incorporation of a super-dimerization domain into the hinge region of an immunoglobulin heavy chain, enabling the combination of all of the components of two IgG antibodies into a single molecule. Using this approach, we generated GEM-DIMER candidates from rituximab and FMC63, the parental anti-CD19 antibody for anti-CD19 scFv used in approved CAR-T cell therapies. Results: CD19/CD20-targeting GEM-DIMER molecules demonstrated binding to both CD19 and CD20 with affinities comparable to the individual parent antibodies. Importantly, CD19/CD20-targeting GEM-DIMER molecules demonstrated robust depletion of human B cells in overnight cultures of whole blood. Moreover, antibody-dependent cellular cytotoxicity (ADCC) was demonstrated in co-cultures of the human B cell lymphoma cell line Raji and human peripheral blood mononuclear cells (PBMC). As expected, due to the presence of dual Fc domains, CD19/CD20-targeting GEM-DIMER molecules exhibited enhanced binding to Fcgamma receptors, further explaining the robust effector functions observed. Conclusions: CD19/CD20-targeting GEM-DIMER molecules are promising candidates to provide efficient depletion of both CD19+ and CD20+ cells, providing potential for broad and deep depletion of B cells with reduced risk of emergence of antigen escape variants. These data support the advancement of CD19/CD20-targeting GEM-DIMER molecules in multiple indications where depletion of CD19+ and/or CD20+ B cells is needed. Preparations for clinical investigation are ongoing. Citation Format: Daniel J. Capon, Nelson L. Chan, Larisa Troitskaya, Marina Fomin, Ursula Edman, Brendon Frank, Benjamin Z. Capon, Brian Law, Steven J. Chapin, Gavin M. Lewis, Malcolm L. Gefter, Juha Punnonen. Beyond antibodies and CAR-T: Topologically-engineered, super-dimeric antibody-like molecules with dual Fc domains for trispecific, bivalent targeting of CD19, CD20, and Fcgamma receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2730.
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Vasquez, Paula A., Caitlin Hult, David Adalsteinsson, Josh Lawrimore, Mark G. Forest, and Kerry Bloom. "Entropy gives rise to topologically associating domains." Nucleic Acids Research 44, no. 12 (June 2, 2016): 5540–49. http://dx.doi.org/10.1093/nar/gkw510.
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Ciabrelli, Filippo, and Giacomo Cavalli. "Chromatin-Driven Behavior of Topologically Associating Domains." Journal of Molecular Biology 427, no. 3 (February 2015): 608–25. http://dx.doi.org/10.1016/j.jmb.2014.09.013.
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Ma, Jingzhen, Qun Sun, Zhao Zhou, Bowei Wen, and Shaomei Li. "A Multi-Scale Residential Areas Matching Method Considering Spatial Neighborhood Features." ISPRS International Journal of Geo-Information 11, no. 6 (May 31, 2022): 331. http://dx.doi.org/10.3390/ijgi11060331.
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Residential areas is one of the basic geographical elements on the map and an important content of the map representation. Multi-scale residential areas matching refers to the process of identifying and associating entities with the same name in different data sources, which can be widely used in map compilation, data fusion, change detection and update. A matching method considering spatial neighborhood features is proposed to solve the complex matching problem of multi-scale residential areas. The method uses Delaunay triangulation to divide complex matching entities in different scales into closed domains through spatial neighborhood clusters, which can obtain many-to-many matching candidate feature sets. At the same time, the geometric features and topological features of the residential areas are fully considered, and the Relief-F algorithm is used to determine the weight values of different similarity features. Then the similarity and spatial neighborhood similarity of the polygon residential areas are calculated, after which the final matching results are obtained. The experimental results show that the accuracy rate, recall rate and F value of the matching method are all above 90%, which has a high matching accuracy. It can identify a variety of matching relationships and overcome the influence of certain positional deviations on matching results. The proposed method can not only take account of the spatial neighborhood characteristics of residential areas, but also identify complex matching relationships in multi-scale residential areas accurately with a good matching effect.
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Moronta-Gines, Macarena, Thomas R. H. van Staveren, and Kerstin S. Wendt. "One ring to bind them – Cohesin’s interaction with chromatin fibers." Essays in Biochemistry 63, no. 1 (March 22, 2019): 167–76. http://dx.doi.org/10.1042/ebc20180064.
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Abstract In the nuclei of eukaryotic cells, the genetic information is organized at several levels. First, the DNA is wound around the histone proteins, to form a structure termed as chromatin fiber. This fiber is then arranged into chromatin loops that can cluster together and form higher order structures. This packaging of chromatin provides on one side compaction but also functional compartmentalization. The cohesin complex is a multifunctional ring-shaped multiprotein complex that organizes the chromatin fiber to establish functional domains important for transcriptional regulation, help with DNA damage repair, and ascertain stable inheritance of the genome during cell division. Our current model for cohesin function suggests that cohesin tethers chromatin strands by topologically entrapping them within its ring. To achieve this, cohesin’s association with chromatin needs to be very precisely regulated in timing and position on the chromatin strand. Here we will review the current insight in when and where cohesin associates with chromatin and which factors regulate this. Further, we will discuss the latest insights into where and how the cohesin ring opens to embrace chromatin and also the current knowledge about the ‘exit gates’ when cohesin is released from chromatin.
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Szabo, Quentin, Frédéric Bantignies, and Giacomo Cavalli. "Principles of genome folding into topologically associating domains." Science Advances 5, no. 4 (April 2019): eaaw1668. http://dx.doi.org/10.1126/sciadv.aaw1668.
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Understanding the mechanisms that underlie chromosome folding within cell nuclei is essential to determine the relationship between genome structure and function. The recent application of “chromosome conformation capture” techniques has revealed that the genome of many species is organized into domains of preferential internal chromatin interactions called “topologically associating domains” (TADs). This chromosome chromosome folding has emerged as a key feature of higher-order genome organization and function through evolution. Although TADs have now been described in a wide range of organisms, they appear to have specific characteristics in terms of size, structure, and proteins involved in their formation. Here, we depict the main features of these domains across species and discuss the relation between chromatin structure, genome activity, and epigenome, highlighting mechanistic principles of TAD formation. We also consider the potential influence of TADs in genome evolution.
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Dekker, Job, and Edith Heard. "Structural and functional diversity of Topologically Associating Domains." FEBS Letters 589, no. 20PartA (September 5, 2015): 2877–84. http://dx.doi.org/10.1016/j.febslet.2015.08.044.
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Stevens, Claire, Leonardo Gonzalez-Smith, Huan Cao, and Suhn K. Rhie. "Abstract 7013: Methyl-Micro-C: simultaneous high-resolution characterization of three-dimensional chromatin structure and the DNA methylome." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7013. http://dx.doi.org/10.1158/1538-7445.am2024-7013.
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Abstract Understanding cancer biology allows for the determination of patient prognosis through biomarkers and predicting treatment sensitivity. For many cancer types, genetic changes have been largely characterized, but the contributions of epigenetic changes, which are also implicated in tumorigenesis, are not yet well understood. Three-dimensional chromatin architecture changes occur throughout tumor development, changing the states and interactions between cis-regulatory elements, overall inducing gene dysregulation. Chromatin structure changes have previously been interrogated using Hi-C, a technique which utilizes restriction enzyme-mediated digestion of chromatin. Although this method is useful, it cannot detect chromatin states of regulatory elements with high sensitivity and resolution due to the use of restriction enzymes that give multi-nucleosome-sized fragments. Micro-C instead uses MNase that preferentially digests accessible regulatory elements, resulting in mono, di, and tri-nucleosome fragments, providing higher-resolution chromatin interaction data, indirectly determining which regulatory elements are active and in proximity to one another. However, spatial proximity of genomic regions are only a piece of the chromatin structure epigenetic story. Partially methylated domains, which are gained or altered throughout tumor development, are reported to co-localize with topologically associating domains, suggesting that they can contribute to chromatin structure alterations. Whole methylome sequencing techniques can be used to determine methylation states of these domains and regulatory regions. Recently, enzyme-mediated methylation sequencing has been shown to induce less DNA damage than the canonical whole-genome bisulfite sequencing, providing a more accurate and comprehensive picture of the DNA methylome. Although DNA methylome data alone can provide information about epigenetic status within genomic regions, overlaying chromatin structure changes at these locations can further corroborate findings. In this way, chromatin structure and DNA methylome data together can provide a more complete picture of cancer epigenetics. However, it is very expensive to sequence at the depth necessary to gain useful information. To address this issue, we developed a technique called Methyl-Micro-C to simultaneously interrogate the DNA methylome while observing chromatin structure in the same sample. Methyl-Micro-C integrates the higher resolution Micro-C method and more comprehensive enzyme-mediated methylation sequencing method together to investigate both the chromatin interactions as well as DNA methylation patterns for the same sample simultaneously. Here, we use Methyl-Micro-C with prostate cancer cells to characterize 3D epigenomic mechanisms that drive prostate carcinogenesis. Citation Format: Claire Stevens, Leonardo Gonzalez-Smith, Huan Cao, Suhn K. Rhie. Methyl-Micro-C: simultaneous high-resolution characterization of three-dimensional chromatin structure and the DNA methylome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7013.
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Viny, Aaron D., Robert L. Bowman, Yu Liu, Vincent-Philippe Lavallee, Shira Eisman, Wenbin Xiao, Benjamin H. Durham, et al. "Stag2 Regulates Hematopoietic Differentiation and Self-Renewal through Alterations in Gene Expression and Topological Control." Blood 134, Supplement_1 (November 13, 2019): 279. http://dx.doi.org/10.1182/blood-2019-123464.
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Cell-type specific transcriptional programs are regulated by the activity of tissue-specific transcription factors and enhancer elements within structurally defined topologically associating domains (TADs). The coordinated and dynamic changes in chromatin architecture are highly regulated as transcriptional output is influenced by chromatin accessibility, histone modification, promoter enhance interactions, and recruitment of transcriptional co-activator complexes. The genes which contribute to transcriptional regulation, including members of the cohesin complex, are frequently mutated in human cancers, including leukemias, Ewing sarcoma, and glioblastoma multiforme. Despite this, the mechanistic role of STAG2 in gene regulation, hematopoietic function, and tumor suppression has not been delineated. We show that somatic Stag2 deletion in hematopoietic stem/progenitor cells (HSPC) results in altered hematopoietic function, increased self-renewal, and impaired differentiation across all three lineages consistent with myelodysplasia. Chromatin immunoprecipitation sequencing of Stag2-deficient HSPCs revealed that Stag2 and Stag1 have both shared and non-redundant cistromes with Stag1/2 common binding sites enriching at TAD boundaries with CTCF occupancy. This maintains TAD integrity in the setting of Stag2 loss of function which we confirmed with Hi-C chromosome capture. High resolution of the Hi-C data at 10kB resolution identified a specific role for Stag2, but not Stag1, in maintaining short-range chromatin interactions, specifically at genes with PU.1 and IRF8 motifs. While co-deletion of Stag2 and Stag1 resulted in synthetic lethality, Stag2 loss alone resulted in decreased chromatin accessibility and reduced transcriptional output at key PU.1 target loci involved in lineage-specification, including reduced Ebf1 and Pax5 expression resulting in impaired B-lineage differentiation. We investigated whether expression of PU.1 could overcome the non-permissive chromatin state at these key downstream targets and rescue hematopoietic differentiation; however, PU.1 expression could not restore Ebf1 expression or B cell differentiation and did not attenuate the serial replating capacity of Stag2 deficient hematopoietic stem/progenitor cells (HSPCs). Given this transcriptional "choke-point" we investigated whether expression of Ebf1 would have a more significant impact on Stag2 deficient cells. Indeed Ebf1 rescue restored B cell colony formation/differentiation in vitro and in vivo and abrogated serial replating of Stag2 deficient HSPCs. These data highlight the non-hierarchical and non-redundant relationship between transcription factors and chromatin architecture and demonstrate a key role for Stag2-regulated local interactions in transcription factor output and hematopoietic differentiation. Nonetheless, the mechanistic underpinnings of the structural basis for transcriptional regulation remain associative. We have recently been able to reduce the cell input for Hi-C assays such that we can now analyze the chromatin architecture of purified populations and model the structural transition from Lin- Sca-1+ Kit+ hematopoietic stem cells to committed granulocyte macrophage precursor cells both in normal hematopoiesis and in the Stag2 deficient setting. Previous studies using in vitro systems have shown that complete cohesin depletion results in the loss of structural loop components; however, cohesin levels are reduced, but not absent, in cancer cells. As such, our studies highlight a key role for locus-specific alterations in gene regulation and DNA interactions in Stag2 deficient cells, which results in altered gene expression and contributes to transformation. Taken together, these data identify a key role for Stag2 loss in transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation. Moreover, we illustrate a critical link between cohesin, chromosomal contacts, and gene regulation that contributes to hematopoietic transformation. Disclosures Viny: Mission Bio: Other: Sponsored travel; Hematology News: Membership on an entity's Board of Directors or advisory committees. Dekker:Arima Genomics: Membership on an entity's Board of Directors or advisory committees. Levine:Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Lilly: Honoraria; Gilead: Consultancy; Novartis: Consultancy; Prelude Therapeutics: Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Loxo: Membership on an entity's Board of Directors or advisory committees.
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Bayard, Quentin, Pierre Cordier, Camille Péneau, Sandrine Imbeaud, Theo Z. Hirsch, Victor Renault, Jean-Charles Nault, et al. "Abstract LB545: Structure, dynamics and consequences of replication stress-induced structural variants in hepatocellular carcinoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB545. http://dx.doi.org/10.1158/1538-7445.am2022-lb545.
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Abstract Oncogene activation leads to replication stress and promotes genomic instability. Here we combine optical mapping and whole genome sequencing to explore in-depth the nature of structural variants (SVs) induced by replication stress in cyclin-activated hepatocellular carcinomas (CCN-HCC). In addition to classical tandem duplications, CCN-HCC display frequent intra- and inter-chromosomal templated insertion cycles (TIC) likely resulting from template switching events. Template switching preferentially involves active topologically associated domains that are close in the 3D genome organization. Template sizes depend on the type of cyclin activation and are coordinated within each TIC. Replication stress induces continuous accumulation of SVs during CCN-HCC progression, fostering the acquisition of new driver alterations and large-scale copy-number changes at TIC borders. Together, this analysis sheds light on the mechanisms, dynamics and consequences of SV accumulation in tumors with oncogene-induced replication stress. Citation Format: Quentin Bayard, Pierre Cordier, Camille Péneau, Sandrine Imbeaud, Theo Z. Hirsch, Victor Renault, Jean-Charles Nault, Jean-Frédéric Blanc, Julien Calderaro, Chantal Desdouets, Jessica Zucman-Rossi, Eric Letouzé. Structure, dynamics and consequences of replication stress-induced structural variants in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB545.
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Atkin, Naomi, Heather Raimer, and Yuh-Hwa Wang. "Broken by the Cut: A Journey into the Role of Topoisomerase II in DNA Fragility." Genes 10, no. 10 (October 12, 2019): 791. http://dx.doi.org/10.3390/genes10100791.
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DNA topoisomerase II (TOP2) plays a critical role in many processes such as replication and transcription, where it resolves DNA structures and relieves torsional stress. Recent evidence demonstrated the association of TOP2 with topologically associated domains (TAD) boundaries and CCCTC-binding factor (CTCF) binding sites. At these sites, TOP2 promotes interactions between enhancers and gene promoters, and relieves torsional stress that accumulates at these physical barriers. Interestingly, in executing its enzymatic function, TOP2 contributes to DNA fragility through re-ligation failure, which results in persistent DNA breaks when unrepaired or illegitimately repaired. Here, we discuss the biological processes for which TOP2 is required and the steps at which it can introduce DNA breaks. We describe the repair processes that follow removal of TOP2 adducts and the resultant broken DNA ends, and present how these processes can contribute to disease-associated mutations. Furthermore, we examine the involvement of TOP2-induced breaks in the formation of oncogenic translocations of leukemia and papillary thyroid cancer, as well as the role of TOP2 and proteins which repair TOP2 adducts in other diseases. The participation of TOP2 in generating persistent DNA breaks and leading to diseases such as cancer, could have an impact on disease treatment and prevention.
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Wang, Hengtao, Meiling Liang, Jiajia Wu, Xia Peng, Kuangzheng Zhu, and Zhuqing Zheng. "Strategies of Integrated Analysis of ATAC-seq and RNA-seq Data." Science of Advanced Materials 16, no. 1 (January 1, 2024): 130–40. http://dx.doi.org/10.1166/sam.2024.4599.
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The ATAC-seq and RNA-seq have been widely used in the epigenomes analysis of mammals. However, there is a lack of comprehensive integrated analysis of ATAC-seq and RNA-seq data. Here, we explored two effective strategies for analyzing ATAC-seq and RNA-seq data using proliferation and differentiation myoblast cells as model. One strategy is a joint analysis by integrating Hi-C data with ATAC-seq and RNA-seq data. The other strategy is to investigate the association between ATAC-seq and RNA-seq data only based on genome physical distance in the case of no availability of Hi-C data. Hi-C data-based integrated analysis showed a strong correlation between genes and distal enhancers, particularly between genes and promoters, within the topologically associated domains (TADs) and chromatin loops. In the absence of Hi-C data, the integrated analysis based on 500 kb physical distance between genes and associated peaks revealed a strong positive correlation between gene expression and chromatin accessibility. Moreover, the function enrichment analysis indicated that both integrated analysis results could reflect the cellular states. Our proposed two integrated analysis strategies combine ATAC-seq and RNA-seq data, which lay a foundation for subsequent epigenetics studies.
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Stilianoudakis, Spiro C., Maggie A. Marshall, and Mikhail G. Dozmorov. "preciseTAD: a transfer learning framework for 3D domain boundary prediction at base-pair resolution." Bioinformatics 38, no. 3 (November 6, 2021): 621–30. http://dx.doi.org/10.1093/bioinformatics/btab743.
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Abstract Motivation Chromosome conformation capture technologies (Hi-C) revealed extensive DNA folding into discrete 3D domains, such as Topologically Associating Domains and chromatin loops. The correct binding of CTCF and cohesin at domain boundaries is integral in maintaining the proper structure and function of these 3D domains. 3D domains have been mapped at the resolutions of 1 kilobase and above. However, it has not been possible to define their boundaries at the resolution of boundary-forming proteins. Results To predict domain boundaries at base-pair resolution, we developed preciseTAD, an optimized transfer learning framework trained on high-resolution genome annotation data. In contrast to current TAD/loop callers, preciseTAD-predicted boundaries are strongly supported by experimental evidence. Importantly, this approach can accurately delineate boundaries in cells without Hi-C data. preciseTAD provides a powerful framework to improve our understanding of how genomic regulators are shaping the 3D structure of the genome at base-pair resolution. Availability and implementation preciseTAD is an R/Bioconductor package available at https://bioconductor.org/packages/preciseTAD/. Supplementary information Supplementary data are available at Bioinformatics online.