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Histone modifications of circulating nucleosomes are associated with changes in cell-free DNA fragmentation patterns. | LitMetric

AI Article Synopsis

  • The study focuses on analyzing cell-free DNA (cfDNA) to determine its tissue origin, which is important for research and diagnostics, utilizing a new technique called FRAGHA that looks at fragmentation patterns linked to histone modifications.
  • The research demonstrated strong correlations between specific histone modification signals, such as H3K27ac, and various medical conditions, including fetal DNA presence in maternal plasma and liver cancer detection.
  • Machine learning algorithms were employed to improve early detection of liver cancer, showcasing how cfDNA fragmentomics can enhance the effectiveness of liquid biopsies in clinical settings.

Article Abstract

The analysis of tissues of origin of cell-free DNA (cfDNA) is of research and diagnostic interest. Many studies focused on bisulfite treatment or immunoprecipitation protocols to assess the tissues of origin of cfDNA. DNA loss often occurs during such processes. Fragmentomics of cfDNA molecules has uncovered a wealth of information related to tissues of origin of cfDNA. There is still much room for the development of tools for assessing contributions from various tissues into plasma using fragmentomic features. Hence, we developed an approach to analyze the relative contributions of DNA from different tissues into plasma, by identifying characteristic fragmentation patterns associated with selected histone modifications. We named this technique as FRAGmentomics-based Histone modification Analysis (FRAGHA). Deduced placenta-specific histone H3 lysine 27 acetylation (H3K27ac)-associated signal correlated well with the fetal DNA fraction in maternal plasma (Pearson's = 0.96). The deduced liver-specific H3K27ac-associated signal correlated with the donor-derived DNA fraction in liver transplantation recipients (Pearson's = 0.92) and was significantly increased in patients with hepatocellular carcinoma (HCC) ( < 0.01, Wilcoxon rank-sum test). Significant elevations of erythroblasts-specific and colon-specific H3K27ac-associated signals were observed in patients with β-thalassemia major and colorectal cancer, respectively. Furthermore, using the fragmentation patterns from tissue-specific H3K27ac regions, a machine learning algorithm was developed to enhance HCC detection, with an area under the curve (AUC) of up to 0.97. Finally, genomic regions with H3K27ac or histone H3 lysine 4 trimethylation (H3K4me3) were found to exhibit different fragmentomic patterns of cfDNA. This study has shed light on the relationship between cfDNA fragmentomics and histone modifications, thus expanding the armamentarium of liquid biopsy.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494292PMC
http://dx.doi.org/10.1073/pnas.2404058121DOI Listing

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