With the exception of lamina-associated domains, the radial organization of chromatin in mammalian cells remains largely unexplored. Here we describe genomic loci positioning by sequencing (GPSeq), a genome-wide method for inferring distances to the nuclear lamina all along the nuclear radius. GPSeq relies on gradual restriction digestion of chromatin from the nuclear lamina toward the nucleus center, followed by sequencing of the generated cut sites. Using GPSeq, we mapped the radial organization of the human genome at 100-kb resolution, which revealed radial patterns of genomic and epigenomic features and gene expression, as well as A and B subcompartments. By combining radial information with chromosome contact frequencies measured by Hi-C, we substantially improved the accuracy of whole-genome structure modeling. Finally, we charted the radial topography of DNA double-strand breaks, germline variants and cancer mutations and found that they have distinctive radial arrangements in A and B subcompartments. We conclude that GPSeq can reveal fundamental aspects of genome architecture.

除了与椎板相关的结构域外，哺乳动物细胞中染色质的径向组织在很大程度上仍未被探索。在这里，我们通过测序（GPSeq）描述基因组位点定位，这是一种全基因组方法，用于推断沿核半径到核层的距离。GPSeq 依赖于从核层向核中心逐渐限制性消化染色质，然后对生成的切割位点进行测序。使用 GPSeq，我们以 100 kb 的分辨率绘制了人类基因组的径向组织图，揭示了基因组和表观基因组特征和基因表达的径向模式，以及 A 和 B 子隔室。通过将径向信息与 Hi-C 测量的染色体接触频率相结合，我们大大提高了全基因组结构建模的准确性。最后，我们绘制了 DNA 双链断裂、种系变异和癌症突变的径向拓扑图，发现它们在 A 和 B 子隔室中具有独特的径向排列。我们得出结论，GPSeq 可以揭示基因组结构的基本方面。