scholarly journals Comparative analysis of 2D and 3D distance measurements to study spatial genome organization

2016 ◽  
Author(s):  
Elizabeth H. Finn ◽  
Gianluca Pegoraro ◽  
Sigal Shachar ◽  
Tom Misteli
Keyword(s):  
Genome Organization ◽  
Spatial Organization ◽  
Theoretical Models ◽  
3D Analysis ◽  
Distance Measurements ◽  
Accuracy And Precision ◽  
Distance Distributions ◽  
Cell Type Specific ◽  
Spatial Genome Organization ◽  
2D And 3D

ABSTRACTThe spatial organization of eukaryotic genomes is non-random, cell-type specific, and has been linked to cellular function. The investigation of spatial organization has traditionally relied extensively on fluorescence microscopy. The validity of the imaging methods used to probe spatial genome organization often depends on the accuracy and precision of distance measurements. Imaging-based measurements may either use 2 dimensional datasets or 3D datasets including the z-axis information in image stacks. Here we compare the suitability of 2D versus 3D distance measurements in the analysis of various features of spatial genome organization. We find in general good agreement between 2D and 3D analysis with higher convergence of measurements as the interrogated distance increases, especially in flat cells. Overall, 3D distance measurements are more accurate than 2D distances, but are also more prone to noise. In particular, z-stacks are prone to error due to imaging properties such as limited resolution along the z-axis and optical aberrations, and we also find significant deviations from unimodal distance distributions caused by low sampling frequency in z. These deviations can be ameliorated by sampling at much higher frequency in the z-direction. We conclude that 2D distances are preferred for comparative analyses between cells, but 3D distances are preferred when comparing to theoretical models in large samples of cells. In general, 2D distance measurements remain preferable for many applications of analysis of spatial genome organization.

scholarly journals Comparative analysis of 2D and 3D distance measurements to study spatial genome organization

Methods ◽  
2017 ◽  
Vol 123 ◽  
pp. 47-55 ◽  
Author(s):  
Elizabeth H. Finn ◽  
Gianluca Pegoraro ◽  
Sigal Shachar ◽  
Tom Misteli
Keyword(s):  
Comparative Analysis ◽  
Genome Organization ◽  
Distance Measurements ◽  
Spatial Genome Organization ◽  
2D And 3D

scholarly journals Revealing Hi-C subcompartments by imputing inter-chromosomal chromatin interactions

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Kyle Xiong ◽  
Jian Ma
Keyword(s):  
Genome Organization ◽  
Cell Types ◽  
Chromatin Interaction ◽  
High Coverage ◽  
Chromatin Interactions ◽  
Genome Wide ◽  
Gm12878 Cell ◽  
Additional Cell ◽  
Cell Type Specific ◽  
Spatial Genome Organization

Abstract Higher-order genome organization and its variation in different cellular conditions remain poorly understood. Recent high-coverage genome-wide chromatin interaction mapping using Hi-C has revealed spatial segregation of chromosomes in the human genome into distinct subcompartments. However, subcompartment annotation, which requires Hi-C data with high sequencing coverage, is currently only available in the GM12878 cell line, making it impractical to compare subcompartment patterns across cell types. Here we develop a computational approach, SNIPER (Subcompartment iNference using Imputed Probabilistic ExpRessions), based on denoising autoencoder and multilayer perceptron classifier to infer subcompartments using typical Hi-C datasets with moderate coverage. SNIPER accurately reveals subcompartments using moderate coverage Hi-C datasets and outperforms an existing method that uses epigenomic features in GM12878. We apply SNIPER to eight additional cell lines and find that chromosomal regions with conserved and cell-type specific subcompartment annotations have different patterns of functional genomic features. SNIPER enables the identification of subcompartments without high-coverage Hi-C data and provides insights into the function and mechanisms of spatial genome organization variation across cell types.

scholarly journals Understanding Spatial Genome Organization: Methods and Insights

2016 ◽  
Vol 14 (1) ◽  
pp. 7-20 ◽  
Author(s):  
Vijay Ramani ◽  
Jay Shendure ◽  
Zhijun Duan
Keyword(s):  
Genome Organization ◽  
Spatial Genome Organization

scholarly journals FIREcaller: Detecting Frequently Interacting Regions from Hi-C Data

2019 ◽  
Author(s):  
Cheynna Crowley ◽  
Yuchen Yang ◽  
Yunjiang Qiu ◽  
Benxia Hu ◽  
Armen Abnousi ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Spatial Organization ◽  
R Package ◽  
Specific Gene ◽  
List Type ◽  
Cell Type ◽  
R Software ◽  
Computational Tools ◽  
Cell Type Specific ◽  
User Friendly

AbstractHi-C experiments have been widely adopted to study chromatin spatial organization, which plays an essential role in genome function. We have recently identified frequently interacting regions (FIREs) and found that they are closely associated with cell-type-specific gene regulation. However, computational tools for detecting FIREs from Hi-C data are still lacking. In this work, we present FIREcaller, a stand-alone, user-friendly R package for detecting FIREs from Hi-C data. FIREcaller takes raw Hi-C contact matrices as input, performs within-sample and cross-sample normalization, and outputs continuous FIRE scores, dichotomous FIREs, and super-FIREs. Applying FIREcaller to Hi-C data from various human tissues, we demonstrate that FIREs and super-FIREs identified, in a tissue-specific manner, are closely related to gene regulation, are enriched for enhancer-promoter (E-P) interactions, tend to overlap with regions exhibiting epigenomic signatures of cis-regulatory roles, and aid the interpretation or GWAS variants. The FIREcaller package is implemented in R and freely available at https://yunliweb.its.unc.edu/FIREcaller.Highlights– Frequently Interacting Regions (FIREs) can be used to identify tissue and cell-type-specific cis-regulatory regions.– An R software, FIREcaller, has been developed to identify FIREs and clustered FIREs into super-FIREs.

scholarly journals Technologies to study spatial genome organization: beyond 3C

2019 ◽  
Author(s):  
Nadine Übelmesser ◽  
Argyris Papantonis
Keyword(s):  
Genome Organization ◽  
Nuclear Organization ◽  
Three Dimensional ◽  
Nuclear Space ◽  
Chromosome Conformation ◽  
Novel Variants ◽  
Cell Processes ◽  
Systematic Biases ◽  
And Function ◽  
Spatial Genome Organization

Abstract The way that chromatin is organized in three-dimensional nuclear space is now acknowledged as a factor critical for the major cell processes, like transcription, replication and cell division. Researchers have been armed with new molecular and imaging technologies to study this structure-to-function link of genomes, spearheaded by the introduction of the ‘chromosome conformation capture’ technology more than a decade ago. However, this technology is not without shortcomings, and novel variants and orthogonal approaches are being developed to overcome these. As a result, the field of nuclear organization is constantly fueled by methods of increasing resolution and/or throughput that strive to eliminate systematic biases and increase precision. In this review, we attempt to highlight the most recent advances in technology that promise to provide novel insights on how chromosomes fold and function.

scholarly journals Mapping 3D genome organization relative to nuclear compartments using TSA-Seq as a cytological ruler

2018 ◽  
Vol 217 (11) ◽  
pp. 4025-4048 ◽  
Author(s):  
Yu Chen ◽  
Yang Zhang ◽  
Yuchuan Wang ◽  
Liguo Zhang ◽  
Eva K. Brinkman ◽  
...  
Keyword(s):  
Genome Organization ◽  
Spatial Organization ◽  
Essential Feature ◽  
K562 Cells ◽  
Housekeeping Genes ◽  
Mapping Method ◽  
Spatial Gradient ◽  
Nuclear Speckles ◽  
Nuclear Compartments ◽  
Genome Wide

While nuclear compartmentalization is an essential feature of three-dimensional genome organization, no genomic method exists for measuring chromosome distances to defined nuclear structures. In this study, we describe TSA-Seq, a new mapping method capable of providing a “cytological ruler” for estimating mean chromosomal distances from nuclear speckles genome-wide and for predicting several Mbp chromosome trajectories between nuclear compartments without sophisticated computational modeling. Ensemble-averaged results in K562 cells reveal a clear nuclear lamina to speckle axis correlated with a striking spatial gradient in genome activity. This gradient represents a convolution of multiple spatially separated nuclear domains including two types of transcription “hot zones.” Transcription hot zones protruding furthest into the nuclear interior and positioning deterministically very close to nuclear speckles have higher numbers of total genes, the most highly expressed genes, housekeeping genes, genes with low transcriptional pausing, and super-enhancers. Our results demonstrate the capability of TSA-Seq for genome-wide mapping of nuclear structure and suggest a new model for spatial organization of transcription and gene expression.

scholarly journals Observable scattered light features from inclined and non-inclined planets embedded in protoplanetary discs

2019 ◽  
Vol 487 (4) ◽  
pp. 5372-5387
Author(s):  
Dylan L Kloster ◽  
M Flock
Keyword(s):  
Surface Density ◽  
Scattered Light ◽  
Intensity Variation ◽  
Theoretical Models ◽  
Upper Atmosphere ◽  
High Mass ◽  
Hydrodynamic Simulations ◽  
3D Simulations ◽  
2D And 3D ◽  
Protoplanetary Discs

ABSTRACT Over the last few years instruments such as VLT/SPHERE and Subaru/HiCIAO have been able to take detailed scattered light images of protoplanetary discs. Many of the features observed in these discs are generally suspected to be caused by an embedded planet, and understanding the cause of these features requires detailed theoretical models. In this work we investigate disc–planet interactions using the pluto code to run 2D and 3D hydrodynamic simulations of protoplanetary discs with embedded 30 and 300 M⊕ planets on both an inclined (i = 2.86°) and non-inclined orbit, using an α-viscosity of 4 × 10−3. We produce synthetic scattered light images of these discs at H-band wavelengths using the radiative transfer code radmc3d. We find that while the surface density evolution in 2D and 3D simulations of inclined and non-inclined planets remain fairly similar, their observational appearance is remarkably different. Most of the features seen in the synthetic H-band images are connected to density variations of the disc at around 3.3 scale heights above and below the mid-plane, which emphasizes the need for 3D simulations. Planets on sustained orbital inclinations disrupt the disc’s upper atmosphere and produce radically different observable features and intensity profiles, including shadowing effects and intensity variation of the order of 10–20 times the surrounding background. The vertical optical depth to the disc mid-plane for H-band wavelengths is τ ≈ 20 in the disc gap created by the high-mass planet. We conclude that direct imaging of planets embedded in the disc remains difficult to observe, even for massive planets in the gap.

scholarly journals An integrated 3-Dimensional Genome Modeling Engine for data-driven simulation of spatial genome organization

2016 ◽  
Vol 26 (12) ◽  
pp. 1697-1709 ◽  
Author(s):  
Przemysław Szałaj ◽  
Zhonghui Tang ◽  
Paul Michalski ◽  
Michal J. Pietal ◽  
Oscar J. Luo ◽  
...  
Keyword(s):  
Genome Organization ◽  
Data Driven ◽  
3 Dimensional ◽  
Spatial Genome Organization

scholarly journals Cu2+-based distance measurements by pulsed EPR provide distance constraints for DNA backbone conformations in solution

2020 ◽  
Vol 48 (9) ◽  
pp. e49-e49 ◽  
Author(s):  
Shreya Ghosh ◽  
Matthew J Lawless ◽  
Hanna J Brubaker ◽  
Kevin Singewald ◽  
Michael R Kurpiewski ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Conformational Changes ◽  
Continuous Wave ◽  
Md Simulations ◽  
Distance Measurements ◽  
Paramagnetic Resonance ◽  
Pulsed Epr ◽  
Distance Distributions ◽  
Dna Backbone ◽  
Double Electron Electron Resonance

Abstract Electron paramagnetic resonance (EPR) has become an important tool to probe conformational changes in nucleic acids. An array of EPR labels for nucleic acids are available, but they often come at the cost of long tethers, are dependent on the presence of a particular nucleotide or can be placed only at the termini. Site directed incorporation of Cu2+-chelated to a ligand, 2,2′dipicolylamine (DPA) is potentially an attractive strategy for site-specific, nucleotide independent Cu2+-labelling in DNA. To fully understand the potential of this label, we undertook a systematic and detailed analysis of the Cu2+-DPA motif using EPR and molecular dynamics (MD) simulations. We used continuous wave EPR experiments to characterize Cu2+ binding to DPA as well as optimize Cu2+ loading conditions. We performed double electron-electron resonance (DEER) experiments at two frequencies to elucidate orientational selectivity effects. Furthermore, comparison of DEER and MD simulated distance distributions reveal a remarkable agreement in the most probable distances. The results illustrate the efficacy of the Cu2+-DPA in reporting on DNA backbone conformations for sufficiently long base pair separations. This labelling strategy can serve as an important tool for probing conformational changes in DNA upon interaction with other macromolecules.

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