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.

人血浆中的游离 DNA (cfDNA) 提供了获取有关其起源的器官或肿瘤病理过程的分子信息的途径。这些 DNA 片段来源于垂死细胞中的片段化染色质，并保留了一些细胞源组蛋白修饰。在这项研究中，我们对携带活性染色质修饰的无细胞核小体进行染色质免疫沉淀，然后对 268 个人类样本进行测序 (cfChIP-seq)。在健康供体中，我们发现骨髓巨核细胞而非成红细胞是 cfDNA 库的主要贡献者。在患有一系列肝病的患者中，我们表明我们可以识别肝细胞转录程序中与病理学相关的变化。在转移性结直肠癌患者中，我们检测到临床相关和患者特异性信息，包括具有转录活性的人表皮生长因子受体 2 (HER2) 扩增。总之，cfChIP-seq 使用低测序深度，提供系统和全基因组信息，可以为诊断提供信息，并促进使用血液样本对生理和病理过程的询问。