ChIP-seq of plasma cell-free nucleosomes identifies gene expression programs of the cells of origin

Ronen Sadeh, Israa Sharkia, Gavriel Fialkoff, Ayelet Rahat, Jenia Gutin, Alon Chappleboim, Mor Nitzan, Ilana Fox-Fisher, Daniel Neiman, Guy Meler, Zahala Kamari, Dayana Yaish, Tamar Peretz, Ayala Hubert, Jonathan E. Cohen, Azzam Salah, Mark Temper, Albert Grinshpun, Myriam Maoz, Samir Abu-GazalaAmi Ben Ya’acov, Eyal Shteyer, Rifaat Safadi, Tommy Kaplan, Ruth Shemer, David Planer, Eithan Galun, Benjamin Glaser, Aviad Zick, Yuval Dor, Nir Friedman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


Cell-free DNA (cfDNA) in human plasma provides access to molecular information about the pathological processes in the organs or tumors from which it originates. These DNA fragments are derived from fragmented chromatin in dying cells and retain some of the cell-of-origin histone modifications. In this study, we applied chromatin immunoprecipitation of cell-free nucleosomes carrying active chromatin modifications followed by sequencing (cfChIP-seq) to 268 human samples. In healthy donors, we identified bone marrow megakaryocytes, but not erythroblasts, as major contributors to the cfDNA pool. In patients with a range of liver diseases, we showed that we can identify pathology-related changes in hepatocyte transcriptional programs. In patients with metastatic colorectal carcinoma, we detected clinically relevant and patient-specific information, including transcriptionally active human epidermal growth factor receptor 2 (HER2) amplifications. Altogether, cfChIP-seq, using low sequencing depth, provides systemic and genome-wide information and can inform diagnosis and facilitate interrogation of physiological and pathological processes using blood samples.

Original languageAmerican English
Pages (from-to)586-598
Number of pages13
JournalNature Biotechnology
Issue number5
StatePublished - May 2021

Bibliographical note

Funding Information:
We thank N. Kaminski, J. Moss, E. Pikarsky, N. Rajewsky, O.J. Rando, A. Regev and members of the Friedman lab for discussions and comments on this manuscript. We thank L. Friedman for help with illustrations and graphics. This work was supported by the European Research Council’s AdG Grants 340712 ‘ChromatinSys’ (to N.F.) and 786575 ‘RxmiRcanceR’ (to E.G.); the Israel Science Foundation’s I-CORE program grant 1796/12 (to T.K. and N.F.) and grants 2612/18 (to N.F.), 3020/20 (to A.G.), 2473/17 (to E.G.) and 486/17 (to E.G.); Israel Ministry of Science and Technology grant 3-14352 (to A.G.); National Institutes of Health grants RM1HG006193 (to N.F.) and CA197081-02 (to E.G.); Deutsche Forschungsgemeinschaft SFB841 (to E.G.); and DKFZ-MOST grant (to E.G.).

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.


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