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

Area of Science:

• Molecular Biology
• Genomics
• Biochemistry

Background:

• Analyzing cell-free DNA (cfDNA) tissue of origin is crucial for research and diagnostics.
• Existing methods like bisulfite treatment or immunoprecipitation often lead to DNA loss.
• cfDNA fragmentomics offers a promising avenue, but tools for assessing tissue contributions are needed.

Purpose of the Study:

• To develop a novel approach for analyzing cfDNA tissue contributions using fragmentomic features.
• To identify characteristic fragmentation patterns associated with specific histone modifications.
• To establish FRAGmentomics-based Histone modification Analysis (FRAGHA) for improved liquid biopsy.

Main Methods:

• Developed FRAGmentomics-based Histone modification Analysis (FRAGHA) to analyze cfDNA fragmentation patterns.
• Identified tissue-specific histone H3 lysine 27 acetylation (H3K27ac) and H3 lysine 4 trimethylation (H3K4me3) associated signals.
• Utilized machine learning algorithms with fragmentation patterns for disease detection enhancement.

Main Results:

• FRAGHA showed strong correlation between placenta-specific H3K27ac signal and fetal DNA fraction (r=0.96).
• Liver-specific H3K27ac signal correlated with donor DNA in transplant recipients (r=0.92) and was elevated in hepatocellular carcinoma (HCC).
• Elevated erythroblast- and colon-specific H3K27ac signals were observed in β-thalassemia major and colorectal cancer, respectively.
• Machine learning model using H3K27ac patterns achieved an AUC of 0.97 for HCC detection.
• Distinct fragmentomic patterns were observed for cfDNA from H3K27ac and H3K4me3 regions.

Conclusions:

• FRAGHA effectively analyzes cfDNA tissue contributions by linking fragmentomics to histone modifications.
• This method demonstrates potential for non-invasive diagnostics in various conditions, including cancer and transplantation.
• The study expands the utility of cfDNA fragmentomics and histone modification analysis in liquid biopsy applications.