Cell-Free DNA Comprises an In Vivo Nucleosome Footprint That Informs Its Tissues-of-Origin

摘要

Biomarkers of immune status and graft function are critical in directing current clinical decision making, particularly after transplantation when the aim is to determine the correct immunosuppressive balance without compromising graft function and survival.1 Similarly, there is an interest in understanding when patients are displaying evidence of immune tolerance that might facilitate complete withdrawal of immunosuppression.2 Currently, graft rejection can only reliably be detected based on biopsies that are invasive and possibly further damaging to an already rejecting organ. Other less invasive biomarkers are therefore likely to be useful. Cell-free DNA (cfDNA) is present in blood plasma and urine and is thought to derive from the apoptosis of normal cells. As cfDNA has a short half-life, its baseline presence ongoing release under physiological conditions. Importantly, cfDNA carries a signature related to its size which may help identify its tissue of origin. In the study by Snyder and colleagues, the cfDNA signature is further refined to be able to identify the tissue of origin with more accuracy while assessing whether the tissue producing the cfDNA is normal. Using deep sequencing of cfDNA, the authors identify that in vivo occupancies of transcription factors are directly footprinted by cfDNA and that nucleosome spacing in regulatory elements and gene bodies correlates with gene expression in hematopoeitic cell types. Previously, it has been shown that allograft rejection may be correlated with cfDNA levels.3 The authors' method in the current study is likely to help identify whether the tissue of origin is of donor or recipient origin. In the future, it will be interesting to investigate whether cfDNA is useful for the identification of graft rejection biomarkers before organ damage occurs, and whether cfDNA may help to identify patients who could be amenable to tapering or even withdrawal of immunosuppression.