Researchers at the Hebrew University of Jerusalem have shown how a simple blood test – cfChIP-seq – can be used to detect a wide range of diseases.
Cell-free DNA (cfDNA) provides access to important molecular information about the pathological processes in the organs or tumours from which it originates. These DNA fragments are derived from dying cells. cfDNA analysis can assess foetal chromosomal aberrations, graft rejection, tumour dynamics and treatment response.
These fragments retain some of the cell-of-origin histone modifications. Histone modification patterns can reflect recent events related to chromatin regulation and activity of RNA polymerase. Utilising chromatin immunoprecipitation and sequencing (ChIP-seq) can provide a genome-wide map of histone modifications and a detailed understanding of the regulatory activity within cells.
During cell death, the genome fragments and chromatin (mostly in the form of nucleosomes) releases into circulation as cell-free nucleosomes (cf-nucleosomes) which retain some histone modifications.
In this study, published in Nature Biotechnology, the team reasoned that capturing and sequencing modified nucleosomes could inform on DNA-related activities. This currently inaccessible epigenetic information extends beyond current cfDNA modalities.
To do this, the team performed chromatin immunoprecipitation of cf-nucleosomes carrying active chromatin modifications followed by sequencing (cfChIP-seq). They applied cfChIP-seq to 268 human samples from more than 100 individuals.
In healthy donors, the team identified bone marrow megakaryocytes, but not erythroblasts, as major contributors to the cfDNA pool. In addition, they found that they could identify pathology-related changes in hepatocyte transcriptional programs in individuals with a range of liver diseases. Finally, in patients with metastatic colorectal carcinomas, they detected clinically relevant and patient-specific information. For example, transcriptionally active HER2 amplifications.
These findings indicate that cfChIP-seq can provide systemic and genome-wide information that can inform diagnosis and facilitate interrogation of processes using blood samples. This approach not only has clear diagnostic benefits, it also is non-invasive and far less expensive than traditional biopsies.
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