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

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

PROVIDER: PRJNA503732 | ENA |

REPOSITORIES: ENA

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

Project description:Methylation 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 using in silico simulations as well as in vitro mixes 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.

| S-EPMC6265251 | biostudies-literature

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

Project description:Genome wide DNA methylation profiling of 59 cfDNA samples, 27 isolated cell populations used in deconvolution of cfDNA samples, and 15 samples used as technical controls.

2018-11-04 | GSE122126 | GEO

CelFiE: Comprehensive cell type decomposition of circulating cell-free DNA

Project description:CelFiE: Comprehensive cell type decomposition of circulating cell-free DNA

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CelFiE: Comprehensive cell type decomposition of circulating cell-free DNA

Project description:Circulating cell-free DNA (cfDNA) in the bloodstream originates from dying cells and is a promising non-invasive biomarker for cell death. Here, we propose an algorithm, CelFiE, to accurately estimate 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 rely on 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 rare cell types composing less than 1% of the total mixture. In a positive control of cfDNA extracted from pregnant and non-pregnant women, CelFiE correctly estimates a large placenta component specifically in pregnant women (p = 4.5x10^-5). In cfDNA from ALS patients and age-matched controls, we observed increased cfDNA concentrations in ALS patients (p = 5.0x10^-3), and CelFiE identified a corresponding increased skeletal muscle component (p = 2.4x10^-3), consistent with muscle impairment characterizing ALS. Together these results show CelFiE may be a useful tool for biomarker discovery and monitoring of degenerative disease progression.

2021-01-12 | GSE164600 | GEO

A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung [SC]

Project description:The lung contains numerous specialized cell-types with distinct roles in tissue function and integrity. To clarify the origins and mechanisms generating cell heterogeneity, we created a comprehensive topographic atlas of early human lung development. Here, we report 83 cell states, several spatially-resolved developmental trajectories and predict cell interactions within defined tissue niches. We integrated scRNA-Seq and spatially resolved transcriptomics into a web-based, open platform for interactive exploration. We show distinct gene expression programs, accompanying sequential events of cell differentiation and maturation of the secretory and neuroendocrine cell-types in proximal epithelium. We define the origin of airway fibroblasts associated with airway smooth muscle in bronchovascular bundles and describe a trajectory of Schwann cell progenitors to intrinsic parasympathetic neurons controlling bronchoconstriction. Our atlas provides a rich resource for further research and a reference for defining deviations from homeostatic and repair mechanisms leading to pulmonary diseases.

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A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung

Project description:A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung

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Unified rhombic lip origins of Group 3 and Group 4 medulloblastoma [atlas]

Project description:Unified rhombic lip origins of Group 3 and Group 4 medulloblastoma [atlas]

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