At the dawn: cell-free DNA fragmentomics and gene regulation.

Epigenetic mechanisms play instrumental roles in gene regulation during embryonic development and disease progression. However, it is challenging to non-invasively monitor the dynamics of epigenomes and related gene regulation at inaccessible human tissues, such as tumours, fetuses and transplanted organs. Circulating cell-free DNA (cfDNA) in peripheral blood provides a promising opportunity to non-invasively monitor the genomes from these inaccessible tissues. The fragmentation patterns of plasma cfDNA are unevenly distributed in the genome and reflect the in vivo gene-regulation status across multiple molecular layers, such as nucleosome positioning and gene expression. In this review, we revisited the computational and experimental approaches that have been recently developed to measure the cfDNA fragmentomics across different resolutions comprehensively. Moreover, cfDNA in peripheral blood is released following cell death, after apoptosis or necrosis, mainly from haematopoietic cells in healthy people and diseased tissues in patients. Several cfDNA-fragmentomics approaches showed the potential to identify the tissues-of-origin in cfDNA from cancer patients and healthy individuals. Overall, these studies paved the road for cfDNA fragmentomics to non-invasively monitor the in vivo gene-regulatory dynamics in both peripheral immune cells and diseased tissues.