scholarly journals The interdependent nature of multi-loci associations can be revealed by 4C-Seq

2015 ◽  
Author(s):  
Tingting Jiang ◽  
Ramya Raviram ◽  
Pedro P Rocha ◽  
Valentina Snetkova ◽  
Charlotte Proudhon ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Population Based ◽  
Data Sets ◽  
Low Resolution ◽  
Chromosome Conformation ◽  
Chromatin Interactions ◽  
Pairwise Interactions ◽  
Capture Techniques ◽  
Transcriptional Output ◽  
Resolution Single

Use of low resolution single cell DNA FISH and population based high resolution chromosome conformation capture techniques have highlighted the importance of pairwise chromatin interactions in gene regulation. However, it is unlikely that these associations act in isolation of other interacting partners within the genome. Indeed, the influence of multi-loci interactions in gene control remains something of an enigma as beyond low-resolution DNA FISH we do not have the appropriate tools to analyze these. Here we present a method that uses standard 4C-seq data to identify multi-loci interactions from the same cell. We demonstrate the feasibility of our method using 4C-seq data sets that identify known pairwise interactions involving the Tcrb and Igk antigen receptor enhancers, in addition to novel tri-loci associations. We further show that enhancer deletions not only interfere with tri-loci interactions in which they participate, but they also disrupt pairwise interactions between other partner enhancers and this disruption is linked to a reduction in their transcriptional output. These findings underscore the functional importance of hubs and provide new insight into chromatin organization as a whole. Our method opens the door for studying multi-loci interactions and their impact on gene regulation in other biological settings.

scholarly journals SisterC: A novel 3C-technique to detect chromatin interactions between and along sister chromatids

2020 ◽  
Author(s):  
Marlies E. Oomen ◽  
Adam K. Hedger ◽  
Jonathan K. Watts ◽  
Job Dekker
Keyword(s):  
Cell Cycle ◽  
Single Strand ◽  
Chromosome Conformation Capture ◽  
Brdu Incorporation ◽  
Chromosome Conformation ◽  
Strand Breaks ◽  
Chromatin Interactions ◽  
Sister Chromatids ◽  
Single Strand Breaks ◽  
Capture Techniques

Abstract Current chromosome conformation capture techniques are not able to distinguish sister chromatids. Here we describe the protocol of SisterC1: a novel Hi-C technique that leverages BrdU incorporation and UV/Hoechst-induced single strand breaks to identify interactions along and between sister chromatids. By synchronizing cells, BrdU is incorporated only on the newly replicated strand, which distinguishes the two sister chromatids2,3. This is followed by Hi-C4 of cells that can be arrested in different stages of the cell cycle, e.g. in mitosis. Before final amplification of the Hi-C library, strands containing BrdU are specifically depleted by UV/Hoechst treatment. SisterC libraries are then sequenced using 50bp paired end reads, followed by mapping using standard Hi-C processing tools. Interactions can then be assigned as inter- or intra-sister interactions based on read orientation.

scholarly journals Identifying regulatory and spatial genomic architectural elements using cell type independent machine and deep learning models

2020 ◽  
Author(s):  
Laura D. Martens ◽  
Oisín Faust ◽  
Liviu Pirvan ◽  
Dóra Bihary ◽  
Shamith A. Samarajiwa
Keyword(s):  
Deep Learning ◽  
Cell Types ◽  
Data Sets ◽  
Chromosome Conformation ◽  
Architectural Elements ◽  
Chromatin Interactions ◽  
Genome Wide ◽  
Chromatin Organisation ◽  
Different Cell Types

AbstractChromosome conformation capture methods such as Hi-C enables mapping of genome-wide chromatin interactions and is a promising technology to understand the role of spatial chromatin organisation in gene regulation. However, the generation and analysis of these data sets at high resolutions remain technically challenging and costly. We developed a machine and deep learning approach to predict functionally important, highly interacting chromatin regions (HICR) and topologically associated domain (TAD) boundaries independent of Hi-C data in both normal physiological states and pathological conditions such as cancer. This approach utilises gradient boosted trees and convolutional neural networks trained on both Hi-C and histone modification epigenomic data from three different cell types. Given only epigenomic modification data these models are able to predict chromatin interactions and TAD boundaries with high accuracy. We demonstrate that our models are transferable across cell types, indicating that combinatorial histone mark signatures may be universal predictors for highly interacting chromatin regions and spatial chromatin architecture elements.

scholarly journals Principles of genome folding into topologically associating domains

2019 ◽  
Vol 5 (4) ◽  
pp. eaaw1668 ◽  
Author(s):  
Quentin Szabo ◽  
Frédéric Bantignies ◽  
Giacomo Cavalli
Keyword(s):  
Size Structure ◽  
Genome Structure ◽  
Cell Nuclei ◽  
Chromosome Conformation ◽  
Chromatin Interactions ◽  
Topologically Associating Domains ◽  
Wide Range ◽  
Genome Activity ◽  
And Function ◽  
Capture Techniques

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.

scholarly journals Algorithmic considerations when analysing capture Hi-C data

2020 ◽  
Vol 5 ◽  
pp. 289
Author(s):  
Linden Disney-Hogg ◽  
Ben Kinnersley ◽  
Richard Houlston
Keyword(s):  
Gene Regulation ◽  
Cell Lines ◽  
Chromosome Conformation Capture ◽  
Chromosome Conformation ◽  
Targeting Efficiency ◽  
Chromatin Interactions ◽  
Genomic Architecture ◽  
Insight Into ◽  
Recent Extension

Chromosome conformation capture methodologies have provided insight into the effect of 3D genomic architecture on gene regulation. Capture Hi-C (CHi-C) is a recent extension of Hi-C that improves the effective resolution of chromatin interactions by enriching for defined regions of biological relevance. The varying targeting efficiency between capture regions, however, introduces bias not present in conventional Hi-C, making analysis more complicated. Here we consider salient features of an algorithm that should be considered in evaluating the performance of a program used to analyse CHi-C data in order to infer meaningful interactions. We use the program CHICAGO to analyse promotor capture Hi-C data generated on 28 different cell lines as a case study.

scholarly journals Lower resolution Laue neutron data yield correct nanocluster formulations

2014 ◽  
Vol 70 (a1) ◽  
pp. C187-C187
Author(s):  
Alison Edwards
Keyword(s):  
Neutron Diffraction ◽  
Single Crystal ◽  
Diffraction Pattern ◽  
Precise Determination ◽  
Data Sets ◽  
X Rays ◽  
Low Resolution ◽  
Neutron Data ◽  
X Ray ◽  
Product Formulation

"The renaissance in Laue studies - at neutron sources - provides us with access to single crystal neutron diffraction data for synthetic compounds without requiring synthesis of prohibitively large amounts of compound or improbably large crystals. Such neutron diffraction studies provide vital data where proof of the presence or absence of hydrogen in particular locations is required and which cannot validly be proved by X-ray studies. Since the commissioning of KOALA at OPAL in 2009[1] we have obtained numerous data sets which demonstrate the vital importance of measuring data even where the extent of the diffraction pattern is at relatively low resolution - especially when compared to that obtainable for the same compound with X-rays. In the Laue experiment performed with a fixed radius detector, data reduction is only feasible for crystals in the ""goldilocks"" zone – where the unit cell is relatively large for the detector, a correspondingly low resolution diffraction pattern in which adjacent spots are less affected by overlap will yield more data against which a structure can be refined than a pattern of higher resolution – one where neighbouring spots overlap rendering both unusable (in our current methodology). Analogous application of powder neutron diffraction in such determinations is also considered. Single crystal neutron diffraction studies of several important compounds (up to 5KDa see figure below)[2] in which precise determination of hydride content by neutron diffraction was pivotal to the final formulation will be presented. The neutron data sets typically possess 20% or fewer unique data at substantially "lower resolution" than the corresponding X-ray data sets. Careful refinement clearly reveals chemical detail which is typically unexplored in related X-ray diffraction studies reporting high profile chemistry despite the synthetic route being one which hydride ought to be considered/excluded in product formulation."

scholarly journals Investigation of the international comparability of population-based routine hospital data set derived comorbidity scores for patients with lung cancer

Thorax ◽  
2017 ◽  
Vol 73 (4) ◽  
pp. 339-349 ◽  
Author(s):  
Margreet Lüchtenborg ◽  
Eva J A Morris ◽  
Daniela Tataru ◽  
Victoria H Coupland ◽  
Andrew Smith ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Survival ◽  
Population Based ◽  
Data Sets ◽  
Hospital Data ◽  
Data Set ◽  
Discharge Data ◽  
International Differences ◽  
Cancer Data ◽  
Comorbidity Scores

IntroductionThe International Cancer Benchmarking Partnership (ICBP) identified significant international differences in lung cancer survival. Differing levels of comorbid disease across ICBP countries has been suggested as a potential explanation of this variation but, to date, no studies have quantified its impact. This study investigated whether comparable, robust comorbidity scores can be derived from the different routine population-based cancer data sets available in the ICBP jurisdictions and, if so, use them to quantify international variation in comorbidity and determine its influence on outcome.MethodsLinked population-based lung cancer registry and hospital discharge data sets were acquired from nine ICBP jurisdictions in Australia, Canada, Norway and the UK providing a study population of 233 981 individuals. For each person in this cohort Charlson, Elixhauser and inpatient bed day Comorbidity Scores were derived relating to the 4–36 months prior to their lung cancer diagnosis. The scores were then compared to assess their validity and feasibility of use in international survival comparisons.ResultsIt was feasible to generate the three comorbidity scores for each jurisdiction, which were found to have good content, face and concurrent validity. Predictive validity was limited and there was evidence that the reliability was questionable.ConclusionThe results presented here indicate that interjurisdictional comparability of recorded comorbidity was limited due to probable differences in coding and hospital admission practices in each area. Before the contribution of comorbidity on international differences in cancer survival can be investigated an internationally harmonised comorbidity index is required.

Abstract 16110: Impact of Institutional Volume on In-hospital Mortality and Resource Utilization Among Patients With Pulmonary Embolism Treated With Catheter Directed Thrombolysis: A Population-Based Cohort Study

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Isaac C Meier ◽  
Beau M Hawkins ◽  
Federico Silva ◽  
TALLA ROUSAN ◽  
Mohan Edupuganti ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Length Of Stay ◽  
Hospital Mortality ◽  
Population Based ◽  
Data Sets ◽  
Percutaneous Approach ◽  
Catheter Directed Thrombolysis ◽  
Procedural Volume ◽  
Icd 10 ◽  
Institutional Volume

Introduction: Catheter-directed thrombolysis (CDT) is an evolving percutaneous approach for the management of acute pulmonary embolism (PE). Contemporary data examining in-hospital outcomes in relation to procedural volume are limited. Methods: Data sets were extracted from the 2016 national readmission database. Using ICD 10 codes, a search was performed to identify all patients hospitalized with a primary or secondary diagnosis of PE who underwent CDT between 1/1/2016 and 12/31/2016. Hospitals were grouped into quartiles by CDT volume and rates of in-hospital mortality, length of stay, and cost were compared across groups. Adjusted associations were examined using multivariable logistic regression. Results and Conclusions: We identified 2,353 unique patients with PE who underwent CDT at 483 hospitals. The median (25th, 75th percentiles) number of CDT procedures per hospital was 3 (1, 6). Mortality rates were 11.4%, 5.3%, 5.6% and 3.8%, respectively, at hospitals in the 1st, 2nd, 3rd and 4th quartile of CDT procedural volume (Figure; p=0.001). Results were unchanged after multivariable adjustment. Median length of stay by quartile was as follows: 6.5, 5, 5, and 4 days (p <0.001). The median cost for the different quartiles was $28,277, $25,953, $25,896, and $23,007 (p <0.001). We found that CDT performed in patients with PE at low-volume hospitals is associated with excess mortality as well as increased length of stay and cost when compared with higher-volume centers. These findings may inform guidance for volume thresholds for utilization of CDT in the management of acute PE.

scholarly journals Rouse model with transient intramolecular contacts on a timescale of seconds recapitulates folding and fluctuation of yeast chromosomes

2019 ◽  
Vol 47 (12) ◽  
pp. 6195-6207 ◽  
Author(s):  
Marius Socol ◽  
Renjie Wang ◽  
Daniel Jost ◽  
Pascal Carrivain ◽  
Cédric Vaillant ◽  
...  
Keyword(s):  
Structural Properties ◽  
Single Particle Tracking ◽  
Chemical Parameters ◽  
Chromosome Conformation ◽  
Formation Reaction ◽  
Rouse Model ◽  
Physico Chemical ◽  
Capture Techniques

Abstract DNA folding and dynamics along with major nuclear functions are determined by chromosome structural properties, which remain, thus far, elusive in vivo. Here, we combine polymer modeling and single particle tracking experiments to determine the physico-chemical parameters of chromatin in vitro and in living yeast. We find that the motion of reconstituted chromatin fibers can be recapitulated by the Rouse model using mechanical parameters of nucleosome arrays deduced from structural simulations. Conversely, we report that the Rouse model shows some inconsistencies to analyze the motion and structural properties inferred from yeast chromosomes determined with chromosome conformation capture techniques (specifically, Hi-C). We hence introduce the Rouse model with Transient Internal Contacts (RouseTIC), in which random association and dissociation occurs along the chromosome contour. The parametrization of this model by fitting motion and Hi-C data allows us to measure the kinetic parameters of the contact formation reaction. Chromosome contacts appear to be transient; associated to a lifetime of seconds and characterized by an attractive energy of –0.3 to –0.5 kBT. We suggest attributing this energy to the occurrence of histone tail-DNA contacts and notice that its amplitude sets chromosomes in ‘theta’ conditions, in which they are poised for compartmentalization and phase separation.

scholarly journals An integrative approach for fine-mapping chromatin interactions

2019 ◽  
Vol 36 (6) ◽  
pp. 1704-1711
Author(s):  
Artur Jaroszewicz ◽  
Jason Ernst
Keyword(s):  
Gene Regulation ◽  
High Resolution ◽  
Biological Significance ◽  
Computational Method ◽  
Supplementary Information ◽  
Integrative Approach ◽  
Genome Architecture ◽  
Open Chromatin ◽  
Chromatin Interactions ◽  
Genome Wide

Abstract Motivation Chromatin interactions play an important role in genome architecture and gene regulation. The Hi-C assay generates such interactions maps genome-wide, but at relatively low resolutions (e.g. 5-25 kb), which is substantially coarser than the resolution of transcription factor binding sites or open chromatin sites that are potential sources of such interactions. Results To predict the sources of Hi-C-identified interactions at a high resolution (e.g. 100 bp), we developed a computational method that integrates data from DNase-seq and ChIP-seq of TFs and histone marks. Our method, χ-CNN, uses this data to first train a convolutional neural network (CNN) to discriminate between called Hi-C interactions and non-interactions. χ-CNN then predicts the high-resolution source of each Hi-C interaction using a feature attribution method. We show these predictions recover original Hi-C peaks after extending them to be coarser. We also show χ-CNN predictions enrich for evolutionarily conserved bases, eQTLs and CTCF motifs, supporting their biological significance. χ-CNN provides an approach for analyzing important aspects of genome architecture and gene regulation at a higher resolution than previously possible. Availability and implementation χ-CNN software is available on GitHub (https://github.com/ernstlab/X-CNN). Supplementary information Supplementary data are available at Bioinformatics online.

Evaluating Percentage-Based Reporting of Glucose-6-Phosphate Dehydrogenase (G6PD) Enzymatic Activity in a National Reference Laboratory: Assessment of Patient Eligibility for Plasmodium vivax Radical Cure Therapy

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S82-S82
Author(s):  
Emilia Calvaresi ◽  
Jonathan Genzen
Keyword(s):  
Normal Activity ◽  
Population Based ◽  
G6pd Activity ◽  
World Health ◽  
Reference Laboratory ◽  
Data Sets ◽  
Radical Cure ◽  
Laboratory Assessment ◽  
Data Set ◽  
Health Organization

Abstract Objectives The World Health Organization recommends measurement of G6PD activity prior to initiation of 8-aminoquinolones for the treatment of P vivax malaria. An estimated 400 million people worldwide have G6PD deficiency, making them susceptible to hemolysis under oxidative stress. A new single-dose therapy (radical cure) for malaria with tafenoquine is contraindicated in patients with <70% normal G6PD activity due to its prolonged circulating half-life. However, most clinical laboratories report G6PD activity in units g/Hb or units/1012 RBC and do not provide percentage of normal activity, making potential eligibility determination challenging. Methods Using an IRB-exempt protocol, a limited data set of consecutive G6PD quantitative results was retrieved from the clinical laboratory’s enterprise data warehouse. Laboratory testing of these specimens was previously performed at 37°C using an automated enzymatic assay (Pointe Scientific) configured on a cobas c501 chemistry analyzer (Roche Diagnostics). Data were assembled to include adults age 18 to 89 years and excluded repeat results from the same patients as well as outliers. Conclusion The final data set included 52,216 results (female, 55.9%, n = 29,173; male, 44.1%, n = 23,043) from 47 US states. An adjusted male median (100% G6PD activity) was derived using an approach proposed by the Bangkok Workshop guidelines (Domingo et al., Malaria Journal, 2013), modified to more accurately differentiate bimodal peaks in population G6PD histograms. The laboratory-specific, adjusted male median was 12.7 U g/Hb and was similar to peak values derived from alternative curve-fitting approaches. Applying this median to gender-specific data sets, 5.4% of males and 3.8% of females were found to have <70% of normal activity (<8.9 U g/Hb). This study demonstrates the feasibility of percentage-based G6PD result reporting in adults; further studies will query percentage-based reporting in pediatric populations. Population-based medians will vary based on G6PD assay type and temperature and should be established by laboratories prior to percentage-based reporting.

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