scholarly journals Predicting CTCF-mediated chromatin loops using CTCF-MP

2018 ◽  
Author(s):  
Ruochi Zhang ◽  
Yuchuan Wang ◽  
Yang Yang ◽  
Yang Zhang ◽  
Jian Ma
Keyword(s):  
Learning Algorithm ◽  
Three Dimensional ◽  
Cell Types ◽  
Ctcf Binding ◽  
Binding Motif ◽  
Chromatin Loop ◽  
Genomic Context ◽  
Motif Pair ◽  
Chromatin Loops ◽  
Single Cell Type

AbstractThe three dimensional organization of chromosomes within the cell nucleus is highly regulated. It is known that CTCF is an important architectural protein to mediate long-range chromatin loops. Recent studies have shown that the majority of CTCF binding motif pairs at chromatin loop anchor regions are in convergent orientation. However, it remains unknown whether the genomic context at the sequence level can determine if a convergent CTCF motif pair is able to form chromatin loop. In this paper, we directly ask whether and what sequence-based features (other than the motif itself) may be important to establish CTCF-mediated chromatin loops. We found that motif conservation measured by “branch-of-origin” that accounts for motif turn-over in evolution is an important feature. We developed a new machine learning algorithm called CTCF-MP based on word2vec to demonstrate that sequence-based features alone have the capability to predict if a pair of convergent CTCF motifs would form a loop. Together with functional genomic signals from CTCF ChIP-seq and DNase-seq, CTCF-MP is able to make highly accurate predictions on whether a convergent CTCF motif pair would form a loop in a single cell type and also across different cell types. Our work represents an important step further to understand the sequence determinants that may guide the formation of complex chromatin architectures.

DeepYY1: a deep learning approach to identify YY1-mediated chromatin loops

2020 ◽  
Author(s):  
Fu-Ying Dao ◽  
Hao Lv ◽  
Dan Zhang ◽  
Zi-Mei Zhang ◽  
Li Liu ◽  
...  
Keyword(s):  
Deep Learning ◽  
Computational Methods ◽  
Learning Algorithm ◽  
Cell Types ◽  
Chromatin Loops ◽  
Deep Learning Algorithm ◽  
Dna Elements ◽  
Chromatin Folding ◽  
User Friendly ◽  
Different Cell Types

Abstract The protein Yin Yang 1 (YY1) could form dimers that facilitate the interaction between active enhancers and promoter-proximal elements. YY1-mediated enhancer–promoter interaction is the general feature of mammalian gene control. Recently, some computational methods have been developed to characterize the interactions between DNA elements by elucidating important features of chromatin folding; however, no computational methods have been developed for identifying the YY1-mediated chromatin loops. In this study, we developed a deep learning algorithm named DeepYY1 based on word2vec to determine whether a pair of YY1 motifs would form a loop. The proposed models showed a high prediction performance (AUCs$\ge$0.93) on both training datasets and testing datasets in different cell types, demonstrating that DeepYY1 has an excellent performance in the identification of the YY1-mediated chromatin loops. Our study also suggested that sequences play an important role in the formation of YY1-mediated chromatin loops. Furthermore, we briefly discussed the distribution of the replication origin site in the loops. Finally, a user-friendly web server was established, and it can be freely accessed at http://lin-group.cn/server/DeepYY1.

scholarly journals Chromatin Domain Organization of the TCRb Locus and Its Perturbation by Ectopic CTCF Binding

2017 ◽  
Vol 37 (9) ◽  
Author(s):  
Pratishtha Rawat ◽  
Manisha Jalan ◽  
Ananya Sadhu ◽  
Abhilasha Kanaujia ◽  
Madhulika Srivastava
Keyword(s):  
Long Range ◽  
Ctcf Binding ◽  
Spatial Proximity ◽  
Chromatin Domain ◽  
Regulation Of Transcription ◽  
Chromatin Loop ◽  
Vdj Recombination ◽  
Chromatin Loops ◽  
Chromatin Interactions ◽  
Tcrb Locus

ABSTRACT CTCF-mediated chromatin interactions influence organization and function of mammalian genome in diverse ways. We analyzed the interactions among CTCF binding sites (CBS) at the murine TCRb locus to discern the role of CTCF-mediated interactions in the regulation of transcription and VDJ recombination. Chromosome conformation capture analysis revealed thymocyte-specific long-range intrachromosomal interactions among various CBS across the locus that were relevant for defining the limit of the enhancer Eb-regulated recombination center (RC) and for facilitating the spatial proximity of TCRb variable (V) gene segments to the RC. Ectopic CTCF binding in the RC region, effected via genetic manipulation, altered CBS-directed chromatin loops, interfered with RC establishment, and reduced the spatial proximity of the RC with Trbv segments. Changes in chromatin loop organization by ectopic CTCF binding were relatively modest but influenced transcription and VDJ recombination dramatically. Besides revealing the importance of CTCF-mediated chromatin organization for TCRb regulation, the observed chromatin loops were consistent with the emerging idea that CBS orientations influence chromatin loop organization and underscored the importance of CBS orientations for defining chromatin architecture that supports VDJ recombination. Further, our study suggests that in addition to mediating long-range chromatin interactions, CTCF influences intricate configuration of chromatin loops that govern functional interactions between elements.

scholarly journals Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline

2017 ◽  
Author(s):  
Vera B Kaiser ◽  
Colin A Semple
Keyword(s):  
Genome Instability ◽  
Large Fraction ◽  
Replication Timing ◽  
Basic Unit ◽  
Mutational Bias ◽  
Binding Motif ◽  
Chromatin Loop ◽  
Single Nucleotide Variants ◽  
Chromatin Loops ◽  
Evolutionary Innovation

ABSTRACTChromatin loops form a basic unit of interphase nuclear organisation, providing contacts between regulatory regions and target promoters, and forming higher level patterns defining self interacting domains. Recent studies have shown that mutations predicted to alter chromatin loops and domains are frequently observed in tumours and can result in the upregulation of oncogenes, but the combinations of selection and mutational bias underlying these observations remains unknown. Here, we explore the unusual mutational landscape associated with chromatin loop anchor points (LAPs), which are located at the base of chromatin loops and form a kinetic trap for cohesin. We show that LAPs are strongly depleted for single nucleotide variants (SNVs) in tumours, which is consistent with their relatively early replication timing. However, despite low SNV rates, LAPs emerge as sites of evolutionary innovation showing enrichment for structural variants (SVs). They harbour an excess of SV breakpoints in cancers, are prone to double strand breaks in somatic cells, and are bound by DNA repair complex proteins. Recurrently disrupted LAPs are often associated with genes annotated with functions in cell cycle transitions. An unexpectedly large fraction of LAPs (16%) also overlap known meiotic recombination hotspot (HSs), and are enriched for the core PRDM9 binding motif, suggesting that LAPs have been foci for diversity generated during recent human evolution. We suggest that the unusual chromatin structure at LAPs underlies the elevated SV rates observed, marking LAPs as sites of regulatory importance but also genomic fragility.

scholarly journals Integration of phased Hi-C and molecular phenotype data to study genetic and epigenetic effects on chromatin looping

2018 ◽  
Author(s):  
William W. Greenwald ◽  
He Li ◽  
Paola Benaglio ◽  
David Jakubosky ◽  
Hiroko Matsui ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Cell Types ◽  
Fold Change ◽  
Chromatin Loop ◽  
Molecular Phenotype ◽  
Specific Expression ◽  
Chromatin Loops ◽  
Phenotype Data ◽  
Number Variation

SummaryWhile genetic variation at chromatin loops is relevant for human disease, the relationships between loop strength, genetics, gene expression, and epigenetics are unclear. Here, we quantitatively interrogate this relationship using Hi-C and molecular phenotype data across cell types and haplotypes. We find that chromatin loops consistently form across multiple cell types and quantitatively vary in strength, instead of exclusively forming within only one cell type. We show that large haplotype loop imbalance is primarily associated with imprinting and copy number variation, rather than genetically driven traits such as allele-specific expression. Finally, across cell types and haplotypes, we show that subtle changes in chromatin loop strength are associated with large differences in other molecular phenotypes, with a 2-fold change in looping corresponding to a 100-fold change in gene expression. Our study suggests that regulatory genetic variation could mediate its effects on gene expression through subtle modification of chromatin loop strength.

scholarly journals Contribution of CTCF binding to transcriptional activity at the HOXA locus in NPM1-mutant AML cells

2020 ◽  
Author(s):  
Reza Ghasemi ◽  
Heidi Struthers ◽  
Elisabeth R. Wilson ◽  
David H. Spencer
Keyword(s):  
Gene Expression ◽  
Transcriptional Activity ◽  
Three Dimensional ◽  
Ctcf Binding ◽  
Chromatin Domain ◽  
Intrinsic Factors ◽  
Chromatin Loops ◽  
Chromatin Interactions ◽  
The Common

AbstractTranscriptional regulation of the HOXA genes is thought to involve CTCF-mediated chromatin loops and the opposing actions of the COMPASS and Polycomb epigenetic complexes. We investigated the role of these mechanisms at the HOXA cluster in AML cells with the common NPM1c mutation, which express both HOXA and HOXB genes. CTCF binding at the HOXA locus is conserved across primary AML samples, regardless of HOXA gene expression, and defines a continuous chromatin domain marked by COMPASS-associated histone H3 trimethylation in NPM1-mutant primary AML samples. Profiling of the three-dimensional chromatin architecture of NPM1-mutant OCI-AML3 cells identified chromatin loops between the active HOXA9-HOXA11 genes and loci in the SNX10 gene and an intergenic region located 1.4Mbp upstream of the HOXA locus. Deletion of CTCF binding sites in OCI-AML3 cells reduced these interactions, but resulted in new, CTCF-independent loops with regions in the SKAP2 gene that were marked by enhancer-associated histone modifications in primary AML samples. HOXA gene expression was maintained in the CTCF deletion mutants, indicating that transcriptional activity at the HOXA locus in NPM1-mutant AML cells does not require long-range CTCF-mediated chromatin interactions, and instead may be driven by intrinsic factors within the HOXA gene cluster.

scholarly journals Predicting three-dimensional genome organization with chromatin states

2018 ◽  
Author(s):  
Yifeng Qi ◽  
Bin Zhang
Keyword(s):  
Genome Organization ◽  
De Novo ◽  
Three Dimensional ◽  
Super Resolution ◽  
Cell Types ◽  
Quantitative Agreement ◽  
Chromosome Conformation ◽  
Chromatin Loops ◽  
Chromatin Folding ◽  
Super Resolution Microscopy

ABSTRACTWe introduce a computational model to simulate chromatin structure and dynamics. Starting from one-dimensional genomics and epigenomics data that are available for hundreds of cell types, this model enables de novo prediction of chromatin structures at five-kilo-base resolution. Simulated chromatin structures recapitulate known features of genome organization, including the formation of chromatin loops, topologically associating domains (TADs) and compartments, and are in quantitative agreement with chromosome conformation capture experiments and super-resolution microscopy measurements. Detailed characterization of the predicted structural ensemble reveals the dynamical flexibility of chromatin loops and the presence of cross-talk among neighboring TADs. Analysis of the model’s energy function uncovers distinct mechanisms for chromatin folding at various length scales.

scholarly journals A CRISPR Screen Identifies Myc-associated Zinc Finger Protein (MAZ) as an Insulator Functioning at CTCF boundaries in Hox Clusters

2020 ◽  
Author(s):  
Havva Ortabozkoyun-Kara ◽  
Pin-Yao Huang ◽  
Hyunwoo Cho ◽  
Varun Narendra ◽  
Gary Leroy ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Cell Types ◽  
Ctcf Binding ◽  
3D Genome ◽  
Finger Protein ◽  
A Genome ◽  
Architectural Organization

AbstractThe essential CCCTC-binding factor (CTCF) is critical to three-dimensional (3D) genome organization. CTCF binding insulates active and repressed genes within the Hox clusters upon differentiation, but such binding does not participate in boundary formation in all cell types, such as embryonic stem cells. We conducted a genome-wide CRISPR knockout screen to identify genes required for CTCF boundary activity at the HoxA cluster, complemented by novel biochemical approaches. This screen identified Myc-associated zinc finger protein (MAZ) as a CTCF insulator co-factor, among other candidates listed herein. MAZ depletion or specific deletion of MAZ motifs within the Hox clusters led to de-repression of posterior Hox genes immediately after CTCF boundaries upon differentiation, which phenocopied deletion of the proximal CTCF motifs. Similar to CTCF, MAZ interacted with the cohesin subunit, RAD21. Upon loss of MAZ, local contacts within topologically associated domains (TADs) were disrupted, as evidenced by HiC analysis. Thus, MAZ is a novel factor sharing insulation properties with CTCF and contributing to the genomic architectural organization.One Sentence SummaryMAZ is identified as an insulator functioning at CTCF boundaries delimiting active and repressed genes at Hox clusters

A sequence-based deep learning approach to predict CTCF-mediated chromatin loop

2021 ◽  
Author(s):  
Hao Lv ◽  
Fu-Ying Dao ◽  
Hasan Zulfiqar ◽  
Wei Su ◽  
Hui Ding ◽  
...  
Keyword(s):  
Computational Models ◽  
Genomic Sequence ◽  
Three Dimensional ◽  
Scoring Function ◽  
Cell Types ◽  
Frequency Component ◽  
Chromatin Interaction ◽  
Chromosome Conformation ◽  
Chromatin Loops ◽  
3D Architecture

Abstract Three-dimensional (3D) architecture of the chromosomes is of crucial importance for transcription regulation and DNA replication. Various high-throughput chromosome conformation capture-based methods have revealed that CTCF-mediated chromatin loops are a major component of 3D architecture. However, CTCF-mediated chromatin loops are cell type specific, and most chromatin interaction capture techniques are time-consuming and labor-intensive, which restricts their usage on a very large number of cell types. Genomic sequence-based computational models are sophisticated enough to capture important features of chromatin architecture and help to identify chromatin loops. In this work, we develop Deep-loop, a convolutional neural network model, to integrate k-tuple nucleotide frequency component, nucleotide pair spectrum encoding, position conservation, position scoring function and natural vector features for the prediction of chromatin loops. By a series of examination based on cross-validation, Deep-loop shows excellent performance in the identification of the chromatin loops from different cell types. The source code of Deep-loop is freely available at the repository https://github.com/linDing-group/Deep-loop.

SEM of Hepatocytes and Biliary Passages in Goldfish Liver

1977 ◽  
Vol 35 ◽  
pp. 556-557
Author(s):  
Waykin Nopanitaya ◽  
Joe W. Grisham ◽  
Johnny L. Carson
Keyword(s):  
Carassius Auratus ◽  
Cell Layer ◽  
Three Dimensional ◽  
Cell Types ◽  
Biliary System ◽  
Fish Food ◽  
Commercial Fish ◽  
Goldfish Carassius Auratus ◽  
Commercial Fish Food

An interesting feature of the goldfish liver is the morphology of the hepatic plate, which is always formed by a two-cell layer of hepatocytes. Hepatic plates of the goldfish liver contain an infrequently seen second type of cell, in the centers of plates between two hepatocytes. A TEH study by Yamamoto (1) demonstrated ultrastructural differences between hepatocytes and centrally located cells in hepatic plates; the latter were classified as ductule cells of the biliary system. None of the previous studies clearly showed a three-dimensional organization of the two cell types described. In the present investigation we utilize SEM to elucidate the arrangement of hepatocytes and bile ductular cells in intralobular plates of goldfish liver.Livers from young goldfish (Carassius auratus), about 6-10 cm, fed commercial fish food were used for this study. Hepatic samples were fixed in 4% buffered paraformaldehyde, cut into pieces, fractured, osmicated, CPD, mounted Au-Pd coated, and viewed by SEM at 17-20 kV. Our observations were confined to the ultrastructure of biliary passages within intralobular plates, ductule cells, and hepatocytes.

Epithelial Organotypic Cultures: A Viable Model to Address Mechanisms of Carcinogenesis by Epitheliotropic Viruses

2018 ◽  
Vol 18 (4) ◽  
pp. 246-255 ◽  
Author(s):  
Lara Termini ◽  
Enrique Boccardo
Keyword(s):  
Three Dimensional ◽  
Cell Types ◽  
Experimental Models ◽  
Biological Research ◽  
Specific Gene ◽  
Specific Cell ◽  
Organotypic Cultures ◽  
Skin Physiology

In vitro culture of primary or established cell lines is one of the leading techniques in many areas of basic biological research. The use of pure or highly enriched cultures of specific cell types obtained from different tissues and genetics backgrounds has greatly contributed to our current understanding of normal and pathological cellular processes. Cells in culture are easily propagated generating an almost endless source of material for experimentation. Besides, they can be manipulated to achieve gene silencing, gene overexpression and genome editing turning possible the dissection of specific gene functions and signaling pathways. However, monolayer and suspension cultures of cells do not reproduce the cell type diversity, cell-cell contacts, cell-matrix interactions and differentiation pathways typical of the three-dimensional environment of tissues and organs from where they were originated. Therefore, different experimental animal models have been developed and applied to address these and other complex issues in vivo. However, these systems are costly and time consuming. Most importantly the use of animals in scientific research poses moral and ethical concerns facing a steadily increasing opposition from different sectors of the society. Therefore, there is an urgent need for the development of alternative in vitro experimental models that accurately reproduce the events observed in vivo to reduce the use of animals. Organotypic cultures combine the flexibility of traditional culture systems with the possibility of culturing different cell types in a 3D environment that reproduces both the structure and the physiology of the parental organ. Here we present a summarized description of the use of epithelial organotypic for the study of skin physiology, human papillomavirus biology and associated tumorigenesis.

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