Abstract
BackgroundThe assessment of cell-free circulating DNA fragments, also known as a "liquid biopsy" of the patient's plasma, is an important source for the discovery and subsequent non-invasive monitoring of cancer and other pathological conditions. Although the nucleosome-guided fragmentation patterns of cell-free DNA (cfDNA) have not yet been studied in detail, non-random representation of cfDNA sequencies may reflect chromatin features in the tissue of origin at gene-regulation level.ResultsIn this study, we investigated the association between epigenetic landscapes of human tissues evident in the patterns of cfDNA in plasma by deep sequencing of human cfDNA samples. We have demonstrated that baseline characteristics of cfDNA fragmentation pattern are in concordance with the ones corresponding to cell lines-derived. To identify the loci differentially represented in cfDNA fragment, we mapped the transcription start sites within the sequenced cfDNA fragments and tested for association of these genomic coordinates with the relative strength and the patterns of gene expressions. Preselected sets of house-keeping and tissue specific genes were used as models for actively expressed and silenced genes. Developed measure of gene regulation was able to differentiate these two sets based on sequencing coverage near gene transcription start site.ConclusionExperimental outcomes suggest that cfDNA retains characteristics previously noted in genome-wide analysis of chromatin structure, in particular, in MNase-seq assays. Thus far the analysis of the DNA fragmentation pattern may aid further developing of cfDNA based biomarkers for a variety of human conditions.
Highlights
The most basic structural unit of the chromatin is a nucleosome that is formed by the binding of DNA to histone octamers containing two monomers for each of the four core histones [1]
Overall distribution of cell-free DNA (cfDNA) fragment lenght reflects apoptotic fragmentation cfDNA samples of two female patients were paired-end sequenced without DNA sonication using Illumina high throuput technology
For the first time, the cfDNA nucleosome fragmentation patterns were analyzed and their potential as a source of novel diagnostic biomakers was demonstrated. It seems that the cfDNA retains characteristics previously noted in genome-wide analysis of chromatin structure
Summary
The most basic structural unit of the chromatin is a nucleosome that is formed by the binding of DNA to histone octamers containing two monomers for each of the four core histones [1]. The nucleosomes play an important role in epigenetic regulation of gene expression programs by competing ends of TSS. The integrity of nucleosomal organization around TSS is essential for the maintenance of the correct gene expression pattern in a given cell. In particluar, this organization provides a fast and reliable way to recruit transcription complexes for genes that have to steadily produce large amounts of their mRNAs, whereas “weak” or “fuzzy” positioned nucleosomes with larger footprints are assciated with higher plasticity of gene expression that allows for rapid changes in mRNAs levels in response to a specific demand [13]. The nucleosome-guided fragmentation patterns of cell-free DNA (cfDNA) have not yet been studied in detail, non-random representation of cfDNA sequencies may reflect chromatin features in the tissue of origin at gene-regulation level
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