scholarly journals The Detailed 3D Multi-Loop Aggregate/Rosette Chromatin Architecture and Functional Dynamic Organization of the Human and Mouse Genomes

2016 ◽  
Author(s):  
Tobias A. Knoch ◽  
Malte Wachsmuth ◽  
Nick Kepper ◽  
Michael Lesnussa ◽  
Anis Abuseiris ◽  
...  
Keyword(s):  
Dna Sequence ◽  
Gene Expression Regulation ◽  
Three Dimensional ◽  
Cell Types ◽  
Scaling Analysis ◽  
Chromatin Architecture ◽  
Novel Approach ◽  
A Genome ◽  
3D Architecture ◽  
Human And Mouse

AbstractThe dynamic three-dimensional chromatin architecture of genomes and its co-evolutionary connection to its function – the storage, expression, and replication of genetic information – is still one of the central issues in biology. Here, we describe the much debated 3D-architecture of the human and mouse genomes from the nucleosomal to the megabase pair level by a novel approach combining selective high-throughput high-resolution chromosomal interaction capture (T2C), polymer simulations, and scaling analysis of the 3D-architecture and the DNA sequence: The genome is compacted into a chromatin quasi-fibre with ∼5±1 nucleosomes/11nm, folded into stable ∼30-100 kbp loops forming stable loop aggregates/rosettes connected by similar sized linkers. Minor but significant variations in the architecture are seen between cell types/functional states. The architecture and the DNA sequence show very similar fine-structured multi-scaling behaviour confirming their co-evolution and the above. This architecture, its dynamics, and accessibility balance stability and flexibility ensuring genome integrity and variation enabling gene expression/regulation by self-organization of (in)active units already in proximity. Our results agree with the heuristics of the field and allow “architectural sequencing” at a genome mechanics level to understand the inseparable systems genomic properties.

scholarly journals The detailed 3D multi-loop aggregate/rosette chromatin architecture and functional dynamic organization of the human and mouse genomes

2016 ◽  
Vol 9 (1) ◽  
Author(s):  
Tobias A. Knoch ◽  
Malte Wachsmuth ◽  
Nick Kepper ◽  
Michael Lesnussa ◽  
Anis Abuseiris ◽  
...  
Keyword(s):  
Dna Sequence ◽  
Gene Expression Regulation ◽  
Three Dimensional ◽  
Cell Types ◽  
Scaling Analysis ◽  
Chromatin Architecture ◽  
Novel Approach ◽  
A Genome ◽  
3D Architecture ◽  
Human And Mouse

Abstract Background The dynamic three-dimensional chromatin architecture of genomes and its co-evolutionary connection to its function—the storage, expression, and replication of genetic information—is still one of the central issues in biology. Here, we describe the much debated 3D architecture of the human and mouse genomes from the nucleosomal to the megabase pair level by a novel approach combining selective high-throughput high-resolution chromosomal interaction capture (T2C), polymer simulations, and scaling analysis of the 3D architecture and the DNA sequence. Results The genome is compacted into a chromatin quasi-fibre with ~5 ± 1 nucleosomes/11 nm, folded into stable ~30–100 kbp loops forming stable loop aggregates/rosettes connected by similar sized linkers. Minor but significant variations in the architecture are seen between cell types and functional states. The architecture and the DNA sequence show very similar fine-structured multi-scaling behaviour confirming their co-evolution and the above. Conclusions This architecture, its dynamics, and accessibility, balance stability and flexibility ensuring genome integrity and variation enabling gene expression/regulation by self-organization of (in)active units already in proximity. Our results agree with the heuristics of the field and allow “architectural sequencing” at a genome mechanics level to understand the inseparable systems genomic properties.

scholarly journals An atlas of silencer elements for the human and mouse genomes

2018 ◽  
Author(s):  
Naresh Doni Jayavelu ◽  
Ajay Jajodia ◽  
Arpit Mishra ◽  
R. David Hawkins
Keyword(s):  
Cell Types ◽  
Regulatory Elements ◽  
Mouse Cell ◽  
Support Vector ◽  
General Strategy ◽  
Gene Promoters ◽  
Genome Wide ◽  
A Genome ◽  
Silencer Elements ◽  
Human And Mouse

ABSTRACTThe study of gene regulation is dominated by a focus on the control of gene activation or controlling an increase in the level of expression. Just as critical is the process of gene repression or silencing. Chromatin signatures have allowed for the global mapping of enhancer cis-regulatory elements, however, the identification of silencer elements by computational or experimental approaches in a genome-wide manner are lacking. We present a simple but powerful computational approach to identify putative silencers genome-wide. We used a series of consortia data to predict silencers in over 100 human and mouse cell or tissue types. We performed several analyses to determine if these elements exhibited characteristics expected of a silencers. Motif enrichment analyses on putative silencers determined that motifs belonging to known transcriptional repressors are enriched, as well as overlapping known transcription repressor binding sites. Leveraging promoter capture HiC data from several human and mouse cell types, we found that over 50% of putative silencer elements are interacting with gene promoters having very low to no expression. Next, to validate our silencer predictions, we quantified silencer activity using massively parallel reporter assays (MPRAs) on 7500 selected elements in K562 cells. We trained a support vector machine model classifier on MPRA data and used it to refine potential silencers in other cell types. We also show that similar to enhancer elements, silencer elements are enriched in disease-associated variants. Our results suggest a general strategy for genome-wide identification and characterization of silencer elements.

scholarly journals Hi–C interaction graph analysis reveals the impact of histone modifications in chromatin shape

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Emre Sefer
Keyword(s):  
Histone Modifications ◽  
Spatial Organization ◽  
Three Dimensional ◽  
Cell Types ◽  
Interaction Graph ◽  
Chromosome Conformation ◽  
A Genome ◽  
Topologically Associated Domains ◽  
Wide Scale ◽  
The Impact

AbstractChromosome conformation capture experiments such as Hi–C map the three-dimensional spatial organization of genomes in a genome-wide scale. Even though Hi–C interactions are not biased towards any of the histone modifications, previous analysis has revealed denser interactions around many histone modifications. Nevertheless, simultaneous effects of these modifications in Hi–C interaction graph have not been fully characterized yet, limiting our understanding of genome shape. Here, we propose ChromatinCoverage and its extension TemporalPrizeCoverage methods to decompose Hi–C interaction graph in terms of known histone modifications. Both methods are based on set multicover with pairs, where each Hi–C interaction is tried to be covered by histone modification pairs. We find 4 histone modifications H3K4me1, H3K4me3, H3K9me3, H3K27ac to be significantly predictive of most Hi–C interactions across species, cell types and cell cycles. The proposed methods are quite effective in predicting Hi–C interactions and topologically-associated domains in one species, given it is trained on another species or cell types. Overall, our findings reveal the impact of subset of histone modifications in chromatin shape via Hi–C interaction graph.

scholarly journals Learning a genome-wide score of human-mouse conservation at the functional genomics level

2020 ◽  
Author(s):  
Soo Bin Kwon ◽  
Jason Ernst
Keyword(s):  
Mouse Model ◽  
Functional Genomics ◽  
Large Scale ◽  
Computational Method ◽  
Functional Genomic ◽  
Model Studies ◽  
Novel Approach ◽  
Genome Wide ◽  
A Genome ◽  
Human And Mouse

AbstractIdentifying genomic regions with functional genomic properties that are conserved between human and mouse is an important challenge in the context of mouse model studies. To address this, we take a novel approach and learn a score of evidence of conservation at the functional genomics level by integrating large-scale information in a compendium of epigenomic, transcription factor binding, and transcriptomic data from human and mouse. The computational method we developed to do this, Learning Evidence of Conservation from Integrated Functional genomic annotations (LECIF), trains a neural network, which is then used to generate a genome-wide score in human and mouse. The resulting LECIF score highlights human and mouse regions with shared functional genomic properties and captures correspondence of biologically similar human and mouse annotations even though it was not explicitly given such information. LECIF will be a resource for mouse model studies.

scholarly journals Transcriptional decomposition reveals active chromatin architectures and cell specific regulatory interactions

2017 ◽  
Author(s):  
Sarah Rennie ◽  
Maria Dalby ◽  
Lucas van Duin ◽  
Robin Andersson
Keyword(s):  
Three Dimensional ◽  
Cell Types ◽  
Considerable Proportion ◽  
Decomposition Approach ◽  
Chromatin Architecture ◽  
Close Relationship ◽  
Tightly Coupled ◽  
Cell Type Specific ◽  
Novel Strategy ◽  
Independent Effects

ABSTRACTTranscriptional regulation is tightly coupled with chromosomal positioning and three-dimensional chromatin architecture. However, it is unclear what proportion of transcriptional activity is reflecting such organisation, how much can be informed by RNA expression alone, and how this impacts disease. Here, we develop a transcriptional decomposition approach separating the proportion of expression associated with genome organisation from independent effects not directly related to genomic positioning.We show that positionally attributable expression accounts for a considerable proportion of total levels and is highly informative of topological associating domain activities and organisation, revealing boundaries and chromatin compartments. Furthermore, expression data alone accurately predicts individual enhancer-promoter interactions, drawing features from expression strength, stabilities, insulation and distance. We further characterise commonalities and differences across predictions in 76 human cell types, observing extensive sharing of domains, yet highly cell-type specific enhancer-promoter interactions and strong enrichments in relevant trait-associated variants. Our work demonstrates a close relationship between transcription and chromatin architecture, presenting a novel strategy and an unprecedented resource for investigating regulatory organisations and interpretations of disease associated genetic variants across cell types.

scholarly journals MyoD is a structure organizer of 3D genome architecture in muscle cells

2020 ◽  
Author(s):  
Qian Chen ◽  
Fengling Chen ◽  
Ruiting Wang ◽  
Minglei Shi ◽  
Antony K. Chen ◽  
...  
Keyword(s):  
Genome Organization ◽  
Three Dimensional ◽  
Muscle Cells ◽  
Cell Types ◽  
Linear Molecule ◽  
Basic Question ◽  
Genome Architecture ◽  
Cell Type ◽  
3D Genome ◽  
A Genome

AbstractThe genome is not a linear molecule of DNA randomly folded in the nucleus, but exists as an organized, three-dimensional (3D) dynamic architecture. Intriguingly, it is now clear that each cell type has a unique and characteristic 3D genome organization that functions in determining cell identity during development. A currently challenging basic question is how cell-type specific 3D genome structures are established during development. Herein, we analyzed 3D genome structures in primary myoblasts and myocytes from MyoD knockout (MKO) and wild type (WT) mice and discovered that MyoD, a pioneer transcription factor (TF), can function as a “genome organizer” that specifies the proper 3D genome architecture unique to muscle cell development. Importantly, we genetically demonstrate that H3K27ac is insufficient for establishing MyoD-induced chromatin loops in muscle cells. The establishment of MyoD’s “architectural role” should have profound impacts on advancing understanding of other pioneer transcription factors in orchestrating lineage specific 3D genome organization during development in a potentially very large number of cell types in diverse organisms.

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.

Three-Dimensional Chromatin Architecture Landscape of Aging and Alzheimer's Disease

2020 ◽  
Author(s):  
Guofeng Meng ◽  
Jialan Huang ◽  
Dong Lu ◽  
Zhenzhen Zhao ◽  
Feng Yu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Three Dimensional ◽  
Chromatin Architecture
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