scholarly journals Comprehensive cell type decomposition of circulating cell-free DNA with CelFiE

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Christa Caggiano ◽  
Barbara Celona ◽  
Fleur Garton ◽  
Joel Mefford ◽  
Brian L. Black ◽  
...  
Keyword(s):  
Biomarker Discovery ◽  
Cell Types ◽  
Cell Type ◽  
Cell Free Dna ◽  
Free Dna ◽  
Noninvasive Biomarker ◽  
Dying Cells ◽  
Als Patients ◽  
Low Coverage ◽  
Circulating Cell Free Dna

AbstractCirculating cell-free DNA (cfDNA) in the bloodstream originates from dying cells and is a promising noninvasive biomarker for cell death. Here, we propose an algorithm, CelFiE, to accurately estimate the relative abundances of cell types and tissues contributing to cfDNA from epigenetic cfDNA sequencing. In contrast to previous work, CelFiE accommodates low coverage data, does not require CpG site curation, and estimates contributions from multiple unknown cell types that are not available in external reference data. In simulations, CelFiE accurately estimates known and unknown cell type proportions from low coverage and noisy cfDNA mixtures, including from cell types composing less than 1% of the total mixture. When used in two clinically-relevant situations, CelFiE correctly estimates a large placenta component in pregnant women, and an elevated skeletal muscle component in amyotrophic lateral sclerosis (ALS) patients, consistent with the occurrence of muscle wasting typical in these patients. Together, these results show how CelFiE could be a useful tool for biomarker discovery and monitoring the progression of degenerative disease.

scholarly journals Estimating the rate of cell type degeneration from epigenetic sequencing of cell-free DNA

2020 ◽  
Author(s):  
Christa Caggiano ◽  
Barbara Celona ◽  
Fleur Garton ◽  
Joel Mefford ◽  
Brian Black ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pregnant Women ◽  
Reference Data ◽  
Cell Types ◽  
The Body ◽  
Cell Type ◽  
Cell Free Dna ◽  
Free Dna ◽  
Als Patients ◽  
Low Coverage

AbstractCirculating cell-free DNA (cfDNA) in the bloodstream originates from dying cells and is a promising non-invasive biomarker for cell death. Here, we develop a method to accurately estimate the relative abundances of cell types contributing to cfDNA. We leverage the distinct DNA methylation profile of each cell type throughout the body. Decomposing the cfDNA mixture is difficult, as fragments from relevant cell types may only be present in a small amount. We propose an algorithm, CelFiE, that estimates cell type proportion from both whole genome cfDNA input and reference data. CelFiE accommodates low coverage data, does not rely on CpG site curation, and estimates contributions from multiple unknown cell types that are not available in reference data. In simulations we show that CelFiE can accurately estimate known and unknown cell type of origin of cfDNA mixtures in low coverage and noisy data. Simulations also demonstrate that we can effectively estimate cfDNA originating from rare cell types composing less than 0.01% of the total cfDNA. To validate CelFiE, we use a positive control: cfDNA extracted from pregnant and non-pregnant women. CelFiE estimates a large placenta component specifically in pregnant women (p = 9.1 × 10−5). Finally, we use CelFiE to decompose cfDNA from ALS patients and age matched controls. We find increased cfDNA concentrations in ALS patients (p = 3.0 × 10−3). Specifically, CelFiE estimates increased skeletal muscle component in the cfDNA of ALS patients (p = 2.6 × 10−3), which is consistent with muscle impairment characterizing ALS. Quantification of skeletal muscle death in ALS is novel, and overall suggests that CelFiE may be a useful tool for biomarker discovery and monitoring of disease progression.

Donor-specific circulating cell free DNA as a noninvasive biomarker of graft injury in heart transplantation

2019 ◽  
Vol 495 ◽  
pp. 590-597 ◽  
Author(s):  
Hada Celicia Macher ◽  
Noelia García-Fernández ◽  
Alejandro Adsuar-Gómez ◽  
Manuel Porras-López ◽  
Antonio González-Calle ◽  
...  
Keyword(s):  
Heart Transplantation ◽  
Cell Free Dna ◽  
Free Dna ◽  
Noninvasive Biomarker ◽  
Circulating Cell Free Dna

scholarly journals Remote immune processes revealed by immune-derived circulating cell-free DNA

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Ilana Fox-Fisher ◽  
Sheina Piyanzin ◽  
Bracha Lea Ochana ◽  
Agnes Klochendler ◽  
Judith Magenheim ◽  
...  
Keyword(s):  
Blood Cell ◽  
B Cell ◽  
Immune Cell ◽  
B Cell Lymphoma ◽  
Cell Types ◽  
Cell Free Dna ◽  
Cell Counts ◽  
Free Dna ◽  
Blood Cell Counts ◽  
Circulating Cell Free Dna

Blood cell counts often fail to report on immune processes occurring in remote tissues. Here we use immune cell type-specific methylation patterns in circulating cell-free DNA (cfDNA) for studying human immune cell dynamics. We characterized cfDNA released from specific immune cell types in healthy individuals (N=242), cross sectionally and longitudinally. Immune cfDNA levels had no individual steady state as opposed to blood cell counts, suggesting that cfDNA concentration reflects adjustment of cell survival to maintain homeostatic cell numbers. We also observed selective elevation of immune-derived cfDNA upon perturbations of immune homeostasis. Following influenza vaccination (N=92), B-cell-derived cfDNA levels increased prior to elevated B-cell counts and predicted efficacy of antibody production. Patients with Eosinophilic Esophagitis (N=21) and B-cell lymphoma (N=27) showed selective elevation of eosinophil and B-cell cfDNA respectively, which were undetectable by cell counts in blood. Immune-derived cfDNA provides a novel biomarker for monitoring immune responses to physiological and pathological processes that are not accessible using conventional methods.

scholarly journals Remote immune processes revealed by immune-derived circulating cell-free DNA

2021 ◽  
Author(s):  
Ilana Fox-Fisher ◽  
Sheina Piyanzin ◽  
Agnes Klochendler ◽  
Bracha Lea Ochana ◽  
Judith Magenheim ◽  
...  
Keyword(s):  
Blood Cell ◽  
B Cell ◽  
Immune Cell ◽  
B Cell Lymphoma ◽  
Cell Types ◽  
Cell Free Dna ◽  
Cell Counts ◽  
Free Dna ◽  
Blood Cell Counts ◽  
Circulating Cell Free Dna

Blood cell counts often fail to report on immune processes occurring in remote tissues. Here we use immune cell type-specific methylation patterns in circulating cell-free DNA (cfDNA) for studying human immune cell dynamics. We characterized cfDNA released from specific immune cell types in healthy individuals (N=242), cross sectionally and longitudinally. Immune cfDNA levels had no individual steady state as opposed to blood cell counts, suggesting that cfDNA concentration reflects adjustment of cell survival to maintain homeostatic cell numbers. We also observed selective elevation of immune-derived cfDNA upon perturbations of immune homeostasis. Following influenza vaccination (N=92), B-cell-derived cfDNA levels increased prior to elevated B-cell counts and predicted efficacy of antibody production. Patients with Eosinophilic Esophagitis (N=21) and B-cell lymphoma (N=27) showed selective elevation of eosinophil and B-cell cfDNA respectively, which were undetectable by cell counts in blood. Immune-derived cfDNA provides a novel biomarker for monitoring immune responses to physiological and pathological processes that are not accessible using conventional methods.

scholarly journals Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Joshua Moss ◽  
Judith Magenheim ◽  
Daniel Neiman ◽  
Hai Zemmour ◽  
Netanel Loyfer ◽  
...  
Keyword(s):  
Human Cell ◽  
Cell Type ◽  
Cell Free Dna ◽  
Free Dna ◽  
Health And Disease ◽  
Circulating Cell Free Dna

scholarly journals Cardiovascular disease biomarkers derived from circulating cell-free DNA methylation

2021 ◽  
Author(s):  
Rafael Ricardo de Castro Cuadrat ◽  
Adelheid Kratzer ◽  
Hector Giral Arnal ◽  
Katarzyna Wreczycka ◽  
Alexander Blume ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Dna Methylation ◽  
Cell Type ◽  
Cell Free Dna ◽  
St Segment Elevation ◽  
Segment Elevation Myocardial Infarction ◽  
Free Dna ◽  
St Segment ◽  
Heart Injury ◽  
Circulating Cell Free Dna

Acute coronary syndromes (ACS) remain a major cause of worldwide mortality. ACS diagnosis is done by a combination of factors, such as electrocardiogram and plasma biomarkers. These biomarkers, however, lack the power to accurately stratify patients into different risk groups. Instead, we used changes in the circulating cell-free DNA (ccfDNA) methylation profiles to estimate the extent of heart injury and the severity of ACS. Our approach relies on the fact that dying cells in acutely damaged tissue release DNA into the blood, causing an increase in the ccfDNA. In addition, each cell type has a distinct DNA methylation profile. We leverage cell type/state specificity of DNA methylation to deconvolute the cell types of origin for ccfDNA and also find DNA methylation-based biomarkers that stratify patient cohorts. The cohorts consisted of healthy subjects, and patients from three ACS conditions: ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA). We have used two cohorts of patients - discovery, and validation, both consisting of the same conditions . We have sequenced the ccfDNA from the discovery cohort using Whole Bisulfite Genome Sequencing (WBGS), to obtain an unbiased overview of plasma DNA methylation profiles. We have found a total of 1,614 differential methylated regions (DMRs) in the three ACS groups. Many of the regions are associated with genes involved in cardiovascular conditions and inflammation. Using linear models we were able to narrow down to 254 DMRs significantly associated with ACS severity. The reduced list of DMRs enabled a more accurate stratification of ACS patients. The predictive power of the DMRs was validated in the confirmation cohort using targeted methylation sequencing of the validation cohort. Measuring methylation on ccfDNA showed promise as a method for estimating the level of heart injury during an acute coronary event, and accurate patient risk stratification. The method is however not limited to acute events, and can be extended to other heart related diseases. It can be used for estimating the status of the disease in patients with chronic states, such as heart failure and coronary artery disease.

scholarly journals Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease

2018 ◽  
Author(s):  
Joshua Moss ◽  
Judith Magenheim ◽  
Daniel Neiman ◽  
Hai Zemmour ◽  
Netanel Loyfer ◽  
...  
Keyword(s):  
Vascular Endothelial Cells ◽  
White Blood Cells ◽  
Cell Types ◽  
Clinical Findings ◽  
The Body ◽  
Unknown Primary ◽  
Cell Free Dna ◽  
Free Dna ◽  
Circulating Cell Free Dna

AbstractMethylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent cell death events in the body. Here, we present an approach for unbiased determination of the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. The method is validated usingin silicosimulations as well asin vitromixes of DNA from different tissue sources at known proportions. We show that plasma cfDNA of healthy donors originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure which can be easily adapted to study the cellular contributors to cfDNA in many settings, opening a broad window into healthy and pathologic human tissue dynamics.

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 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.

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