Extracting regulatory active chromatin footprint from cell-free DNA

Area of Science:

• Genomics
• Epigenetics
• Molecular Biology

Background:

• Cell-free DNA (cfDNA) is crucial in precision medicine, but current assays struggle to capture active transcriptional programs and disease heterogeneity.
• Existing cfDNA analysis primarily focuses on nucleosomal fragments, limiting insights into dynamic gene regulation.

Purpose of the Study:

• To develop a non-invasive method for enriching and analyzing active chromatin fragments (cfDNA_ac) in peripheral blood.
• To correlate cfDNA_ac signals with genomic regulatory elements and gene expression patterns.

Main Methods:

• Developed a platform to isolate and quantify active chromatin fragments (cfDNA_ac) from cfDNA in blood.
• Differentiated cfDNA_ac from nucleosomal cfDNA (cfDNA_nuc) to identify specific genomic features.
• Correlated cfDNA_ac signals with RNA polymerase II activity, circadian gene expression, and whole blood gene expression data (GTEx).

Main Results:

• Successfully deconvoluted cfDNA_ac signals, linking them to regulatory elements like enhancers and promoters.
• Demonstrated strong correlations between cfDNA_ac counts and RNA polymerase II activity.
• Observed distinct cfDNA_ac expression patterns for circadian genes and strong correlations with GTEx whole blood gene expression levels.

Conclusions:

• cfDNA_ac analysis provides a novel, non-invasive window into epigenomics and gene expression from peripheral blood.
• This approach significantly enhances the potential of cfDNA for diverse clinical applications in precision medicine.
• The findings pave the way for more comprehensive disease diagnostics by capturing active transcriptional states.