scholarly journals FinaleDB: a browser and database of cell-free DNA fragmentation patterns

2020 ◽  
Author(s):  
Haizi Zheng ◽  
Michelle S Zhu ◽  
Yaping Liu
Keyword(s):  
Molecular Mechanisms ◽  
Cell Types ◽  
Cell Free Dna ◽  
Link Type ◽  
Diagnosis And Prognosis ◽  
Dna Database ◽  
Free Dna ◽  
Genome Wide ◽  
Fragmentation Patterns ◽  
Different Cell Types

AbstractSummaryCirculating cell-free DNA (cfDNA) is a promising biomarker for the diagnosis and prognosis of many diseases, including cancer. The genome-wide non-random fragmentation patterns of cfDNA are associated with the nucleosomal protection, epigenetic environment, and gene expression in the cell types that contributed to cfDNA. However, current progress on the development of computational methods and understanding of molecular mechanisms behind cfDNA fragmentation patterns is significantly limited by the controlled-access of cfDNA whole-genome sequencing (WGS) dataset. Here, we present FinaleDB (FragmentatIoN AnaLysis of cEll-free DNA DataBase), a comprehensive database to host thousands of uniformly processed and curated de-identified cfDNA WGS datasets across different pathological conditions. Furthermore, FinaleDB comes with a fragmentation genome browser, from which users can seamlessly integrate thousands of other omics data in different cell types to experience a comprehensive view of both gene-regulatory landscape and cfDNA fragmentation patterns.Availability and implementationFinaleDB service: http://finaledb.research.cchmc.org/ FinaleDB source code: https://github.com/epifluidlab/finaledb_portal and https://github.com/epifluidlab/[email protected]

scholarly journals FinaleDB: a browser and database of cell-free DNA fragmentation patterns

2020 ◽  
Author(s):  
Haizi Zheng ◽  
Michelle S Zhu ◽  
Yaping Liu
Keyword(s):  
Molecular Mechanisms ◽  
Cell Types ◽  
Supplementary Information ◽  
Cell Free Dna ◽  
Diagnosis And Prognosis ◽  
Dna Database ◽  
Free Dna ◽  
Genome Wide ◽  
Fragmentation Patterns ◽  
Different Cell Types

Abstract Summary Circulating cell-free DNA (cfDNA) is a promising biomarker for the diagnosis and prognosis of many diseases, including cancer. The genome-wide non-random fragmentation patterns of cfDNA are associated with the nucleosomal protection, epigenetic environment, and gene expression in the cell types that contributed to cfDNA. However, current progress on the development of computational methods and understanding of molecular mechanisms behind cfDNA fragmentation patterns is significantly limited by the controlled-access of cfDNA whole-genome sequencing (WGS) dataset. Here, we present FinaleDB (FragmentatIoN AnaLysis of cEll-free DNA DataBase), a comprehensive database to host thousands of uniformly processed and curated de-identified cfDNA WGS datasets across different pathological conditions. Furthermore, FinaleDB comes with a fragmentation genome browser, from which users can seamlessly integrate thousands of other omics data in different cell types to experience a comprehensive view of both gene-regulatory landscape and cfDNA fragmentation patterns. Availability and implementation FinaleDB service: http://finaledb.research.cchmc.org/. FinaleDB source code: https://github.com/epifluidlab/finaledb_portal, https://github.com/epifluidlab/finaledb_workflow Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals The effect of pre-analytical and physiological variables on cell-free DNA fragmentation.

2021 ◽  
Author(s):  
Ymke van der Pol ◽  
Norbert Moldovan ◽  
Sandra Verkuijlen ◽  
Jip Ramaker ◽  
Dries Boers ◽  
...  
Keyword(s):  
Biological Properties ◽  
Physiological Factors ◽  
Cell Free Dna ◽  
Physiological Variables ◽  
Processing Times ◽  
Free Dna ◽  
Genome Wide ◽  
Collection Tube ◽  
Fragmentation Patterns ◽  
The Impact

Assays that account for the biological properties and fragmentation of cell-free DNA (cfDNA) can improve the performance of liquid biopsy. However, pre-analytic and physiological differences between individuals on fragmentomic analysis are poorly defined. We analyzed the impact of collection tube, plasma processing time and physiology on the size distribution of cfDNA, their genome-wide representation and sequence diversity at the cfDNA fragment-ends using shallow Whole Genome Sequencing. We observed that using different stabilizing collection tubes, or processing times does not affect the cfDNA fragment sizes, but can impact the genome-wide fragmentation patterns and fragment-end sequences of cfDNA. In addition, beyond differences depending on the gender, the physiological conditions tested between 63 individuals (age, body mass index, use of medication and chronic conditions) minimally influenced the outcome of fragmentomic methods. Our results highlight that fragmentomic approaches have potential for implementation in the clinic, pending clear traceability of analytical and physiological factors.

scholarly journals The Detection of Cancer Epigenetic Traces in Cell-Free DNA

2021 ◽  
Vol 11 ◽  
Author(s):  
Anastasia P. Koval ◽  
Konstantin A. Blagodatskikh ◽  
Nikolay E. Kushlinskii ◽  
Dmitry S. Shcherbo
Keyword(s):  
Blood Circulation ◽  
Cell Types ◽  
Parental Cell ◽  
Liquid Biopsies ◽  
Cell Free Dna ◽  
Free Dna ◽  
Reliable Detection ◽  
Fragmentation Patterns ◽  
Dying Cells ◽  
Remarkable Progress

Nucleic acid fragments found in blood circulation originate mostly from dying cells and carry signs pointing to specific features of the parental cell types. Deciphering these clues may be transformative for numerous research and clinical applications but strongly depends on the development and implementation of robust analytical methods. Remarkable progress has been achieved in the reliable detection of sequence alterations in cell-free DNA while decoding epigenetic information from methylation and fragmentation patterns requires more sophisticated approaches. This review discusses the currently available strategies for detecting and analyzing the epigenetic marks in the liquid biopsies.

scholarly journals Sub-nucleosomal organization in urine cell-free DNA

2019 ◽  
Author(s):  
Havell Markus ◽  
Jun Zhao ◽  
Tania Contente-Cuomo ◽  
Elizabeth Raupach ◽  
Ahuva Odenheimer-Bergman ◽  
...  
Keyword(s):  
Nucleosome Occupancy ◽  
Area Under The Curve ◽  
Wide Distribution ◽  
Cancer Diagnostics ◽  
Cell Of Origin ◽  
Cell Free Dna ◽  
Noninvasive Diagnostics ◽  
Free Dna ◽  
Genome Wide ◽  
Fragmentation Patterns

AbstractCell-free DNA (cfDNA) in urine is a promising analyte for noninvasive diagnostics. However, urine cfDNA is highly fragmented and whether characteristics of these fragments reflect underlying genomic architecture is unknown. Here, we perform comprehensive characterization of fragmentation patterns in urine cfDNA. We show modal size and genome-wide distribution of urine cfDNA fragments are consistent with transient protection from degradation by stable intermediates of nucleosome disassembly. Genome-wide nucleosome occupancy and fragment sizes in urine cfDNA are informative of cell of origin and renal epithelial cells are amongst the highest contributors in urine. Compared to a nucleosome occupancy map based on control urine samples, we observe a higher fraction of fragments with aberrant ends in cancer patients, distinguishing cancer samples with an area under the curve of 0.89. Our results demonstrate sub-nucleosomal organization in urine cfDNA and are proof-of-principle that genome-wide fragmentation analysis of urine cfDNA can enable cancer diagnostics.

scholarly journals Changes ofKEAP1/NRF2andIKB/NF-κB Expression Levels Induced by Cell-Free DNA in Different Cell Types

2018 ◽  
Vol 2018 ◽  
pp. 1-17 ◽  
Author(s):  
Svetlana V. Kostyuk ◽  
Lev N. Porokhovnik ◽  
Elizaveta S. Ershova ◽  
Elena M. Malinovskaya ◽  
Marina S. Konkova ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Gc Content ◽  
Cell Types ◽  
Cell Free Dna ◽  
Differentiated Cells ◽  
Free Dna ◽  
Molecular Pattern ◽  
Mitochondrial Origin ◽  
Dying Cells ◽  
Different Cell Types

Cell-free DNA (cfDNA) is a circulating DNA of nuclear and mitochondrial origin mainly derived from dying cells. Recent studies have shown that cfDNA is a stress signaling DAMP (damage-associated molecular pattern) molecule. We report here that the expression profiles of cfDNA-induced factors NRF2 and NF-κB are distinct depending on the target cell’s type and the GC-content and oxidation rate of the cfDNA. Stem cells (MSC) have shown higher expression ofNRF2without inflammation in response to cfDNA. In contrast, inflammatory response launched by NF-κB was dominant in differentiated cells HUVEC, MCF7, and fibroblasts, with a possibility of transition to massive apoptosis. In each cell type examined, the response for oxidized cfDNA was more acute with higher peak intensity and faster resolution than that for nonoxidized cfDNA. GC-rich nonoxidized cfDNA evoked a weaker and prolonged response with proinflammatory component (NF-κB) as predominant. The exploration of apoptosis rates after adding cfDNA showed that cfDNA with moderately increased GC-content and lightly oxidized DNA promoted cell survival in a hormetic manner. Novel potential therapeutic approaches are proposed, which depend on the current cfDNA content: either preconditioning with low doses of cfDNA before a planned adverse impact or eliminating (binding, etc.) cfDNA when its content has already become high.

Genome-wide cell-free DNA fragmentation profiling for early cancer detection.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3018-3018
Author(s):  
Alessandro Leal ◽  
Stephen Cristiano ◽  
Jillian Phallen ◽  
Jacob Fiksel ◽  
Vilmos Adleff ◽  
...  
Keyword(s):  
Dna Fragmentation ◽  
White Blood Cells ◽  
Targeted Sequencing ◽  
Healthy Individuals ◽  
Cell Free Dna ◽  
Patients With Cancer ◽  
Molecular Features ◽  
Free Dna ◽  
Genome Wide ◽  
Fragmentation Patterns

3018 Background: Analyses of cell-free DNA (cfDNA) in the blood provide a noninvasive diagnostic avenue for patients with cancer. However, cfDNA analyses have largely focused on targeted sequencing of specific genes, and the characteristics of the origins and molecular features of cfDNA are poorly understood. We developed an ultrasensitive approach that allows simultaneous examination of a large number of abnormalities in cfDNA through genome-wide analysis of fragmentation patterns. Methods: We used a machine learning model to examined cfDNA fragmentation profiles of 236 patients with largely localized breast, colorectal, lung, ovarian, pancreatic, gastric, or bile duct cancer and 245 healthy individuals. Estimation of performance was determined by ten-fold cross validation repeated ten times. Results: cfDNA profiles of healthy individuals reflected nucleosomal patterns of white blood cells, while patients with cancer had altered fragmentation patterns. The degree of abnormality in fragmentation profiles during therapy closely matched levels of mutant allele fractions in cfDNA as determined using ultra-deep targeted sequencing. The sensitivity of detection ranged from 57% to > 99% among the seven cancer types at 98% specificity, with an overall AUC of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cfDNA analyses detected 91% of cancer patients. Conclusions: This effort is the first study to demonstrate genome-wide cell-free DNA fragmentation abnormalities in patients with cancer. Results of these analyses highlight important properties of cfDNA and provide a facile approach for screening, early detection, and monitoring of human cancer.

scholarly journals HiC-Spector: A matrix library for spectral and reproducibility analysis of Hi-C contact maps

2016 ◽  
Author(s):  
Koon-Kiu Yan ◽  
Galip Guürkan Yardimci ◽  
William S. Noble ◽  
Mark Gerstein
Keyword(s):  
Spectral Analysis ◽  
Data Structures ◽  
Spectral Decomposition ◽  
Source Code ◽  
Cell Types ◽  
Proximity Ligation ◽  
Contact Maps ◽  
Link Type ◽  
Genome Wide ◽  
Different Cell Types

AbstractSummaryGenome-wide proximity ligation based assays like Hi-C have opened a window to the 3D organization of the genome. In so doing, they present data structures that are different from conventional 1D signal tracks. To exploit the 2D nature of Hi-C contact maps, matrix techniques like spectral analysis are particularly useful. Here, we present HiC-spector, a collection of matrix-related functions for analyzing Hi-C contact maps. In particular, we introduce a novel reproducibility metric for quantifying the similarity between contact maps based on spectral decomposition. The metric successfully separates contact maps mapped from Hi-C data coming from biological replicates, pseudo-replicates and different cell types.AvailabilitySource code in Julia and the documentation of HiC-spector can be freely obtained athttps://github.com/gersteinlab/[email protected]

scholarly journals Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types

2021 ◽  
Vol 7 (3) ◽  
pp. eabd9036
Author(s):  
Sara Saez-Atienzar ◽  
Sara Bandres-Ciga ◽  
Rebekah G. Langston ◽  
Jonggeol J. Kim ◽  
Shing Wan Choi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Membrane Trafficking ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Polygenic Risk Score ◽  
Genome Wide ◽  
Genome Wide Data ◽  
Data Driven Approach ◽  
Single Nucleus ◽  
Lateral Sclerosis

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, MAPKAPK3, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.

scholarly journals MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1074
Author(s):  
Giuseppina Divisato ◽  
Silvia Piscitelli ◽  
Mariantonietta Elia ◽  
Emanuela Cascone ◽  
Silvia Parisi
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Embryonic Stem ◽  
Cell Types ◽  
Cancer Development ◽  
Special Focus ◽  
Self Renewal ◽  
Mesenchymal Transition ◽  
Different Cell Types

Embryonic stem cells (ESCs) have the extraordinary properties to indefinitely proliferate and self-renew in culture to produce different cell progeny through differentiation. This latter process recapitulates embryonic development and requires rounds of the epithelial–mesenchymal transition (EMT). EMT is characterized by the loss of the epithelial features and the acquisition of the typical phenotype of the mesenchymal cells. In pathological conditions, EMT can confer stemness or stem-like phenotypes, playing a role in the tumorigenic process. Cancer stem cells (CSCs) represent a subpopulation, found in the tumor tissues, with stem-like properties such as uncontrolled proliferation, self-renewal, and ability to differentiate into different cell types. ESCs and CSCs share numerous features (pluripotency, self-renewal, expression of stemness genes, and acquisition of epithelial–mesenchymal features), and most of them are under the control of microRNAs (miRNAs). These small molecules have relevant roles during both embryogenesis and cancer development. The aim of this review was to recapitulate molecular mechanisms shared by ESCs and CSCs, with a special focus on the recently identified classes of microRNAs (noncanonical miRNAs, mirtrons, isomiRs, and competitive endogenous miRNAs) and their complex functions during embryogenesis and cancer development.

scholarly journals Aging-associated distinctive DNA methylation changes of LINE-1 retrotransposons in pure cell-free DNA from human blood

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Wardah Mahmood ◽  
Lars Erichsen ◽  
Pauline Ott ◽  
Wolfgang A. Schulz ◽  
Johannes C. Fischer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Free Dna ◽  
The Past ◽  
Free Dna ◽  
Genome Wide ◽  
Cancerous Cell ◽  
Pure Cell ◽  
Epigenetic Biomarker ◽  
Methylation Patterns ◽  
Cancerous Cells

AbstractLINE-1 hypomethylation of cell-free DNA has been described as an epigenetic biomarker of human aging. However, in the past, insufficient differentiation between cellular and cell-free DNA may have confounded analyses of genome-wide methylation levels in aging cells. Here we present a new methodological strategy to properly and unambiguously extract DNA methylation patterns of repetitive, as well as single genetic loci from pure cell-free DNA from peripheral blood. Since this nucleic acid fraction originates mainly in apoptotic, senescent and cancerous cells, this approach allows efficient analysis of aged and cancerous cell-specific DNA methylation patterns for diagnostic and prognostic purposes. Using this methodology, we observe a significant age-associated erosion of LINE-1 methylation in cfDNA suggesting that the threshold of hypomethylation sufficient for relevant LINE-1 activation and consequential harmful retrotransposition might be reached at higher age. We speculate that this process might contribute to making aging the main risk factor for many cancers.

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