人类基因组中核小体的位置确定了原始染色质结构，并调控对调控区域的进入。然而，关于原发性癌细胞中核小体占位异常及其影响的基因组范围信息较少。在本研究中，我们在慢性淋巴细胞白血病（CLL）患者和健康个体的外周B细胞中进行了基因组范围高分辨率核小体图谱的单碱基分辨率比较。我们的研究揭示了CLL中核小体定位的显著变化。总体而言，CLL中核小体之间的间距 - 核小体重复长度（NRL） - 缩短了。这种效应在激进的IGHV未突变亚型中更加明显。特定位点的核小体占位变化与活性染色质重塑和DNA甲基化减少密切相关。CLL中失去或获得的核小体标记了3D染色质组织者（如CTCF）以及与免疫应答相关的转录因子的差异性结合，并揭示了表观遗传失调的机制。在癌症特异性区域中进行的核小体占位主成分分析允许将样本分为不同的癌症亚型和正常对照组。此外，与基于DNA甲基化或基因表达的方法相比，根据核小体占位的差异可更好地将患者划分为CLL亚型。因此，核小体定位构成了解析疾病进展分子机制并对患者进行分层的新方法。此外，我们预计在我们的研究中检测到的全局核小体重新定位，如NRL的变化，可以用于基于细胞外DNA的液体活检应用，以对患者进行分层和监测疾病进展。由Cold Spring Harbor Laboratory Press出版。

The location of nucleosomes in the human genome determines the primary chromatin structure and regulates access to regulatory regions. However, genome-wide information on deregulated nucleosome occupancy and its implications in primary cancer cells is scarce. Here, we conducted a genome-wide comparison of high-resolution nucleosome maps in peripheral-blood B cells from patients with chronic lymphocytic leukaemia (CLL) and healthy individuals at single base pair resolution. Our investigation uncovered significant changes of nucleosome positioning in CLL. Globally, the spacing between nucleosomes - the nucleosome repeat length (NRL) - was shortened in CLL. This effect was stronger in the more aggressive IGHV-unmutated than in the IGHV-mutated CLL subtype. Changes in nucleosome occupancy at specific sites were linked to active chromatin remodelling and reduced DNA methylation. Nucleosomes lost or gained in CLL marked differential binding of 3D chromatin organisers such as CTCF as well as immune response-related transcription factors and delineated mechanisms of epigenetic deregulation. The principal component analysis of nucleosome occupancy in cancer-specific regions allowed classification of samples between cancer subtypes and normal controls. Furthermore, patients could be better assigned to CLL subtypes according to differential nucleosome occupancy than based on DNA methylation or gene expression. Thus, nucleosome positioning constitutes a novel readout to dissect molecular mechanisms of disease progression and to stratify patients. Furthermore, we anticipate that the global nucleosome repositioning detected in our study, such as changes in the NRL, can be exploited for liquid biopsy applications based on cell-free DNA to stratify patients and monitor disease progression.Published by Cold Spring Harbor Laboratory Press.