GPSeq reveals the radial organization of chromatin in the cell nucleus

• Published in: Nature biotechnology Vol. 38; no. 10; pp. 1184 - 1193
• Main Authors: Girelli, Gabriele, Custodio, Joaquin, Kallas, Tomasz, Agostini, Federico, Wernersson, Erik, Spanjaard, Bastiaan, Mota, Ana, Kolbeinsdottir, Solrun, Gelali, Eleni, Crosetto, Nicola, Bienko, Magda
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2020; Nature Publishing Group
• Subjects: 631/1647/2210/2211; 631/1647/514/2254; 631/337/100/101; 631/80/386; Agriculture; Bioinformatics; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Cell nuclei; Cell Nucleus - genetics; Cells; Chromatin; Chromatin - genetics; Chromosomes; Deoxyribonucleic acid; DNA; DNA damage; DNA fragmentation; Epigenetic inheritance; Epigenetics; Epigenomics; Gene expression; Gene Expression Regulation - genetics; Gene sequencing; Genes; Genetic aspects; Genome, Human - genetics; Genomes; Genomics; High-Throughput Nucleotide Sequencing; Humans; Life Sciences; Mammalian cells; Mammals; Medicin och hälsovetenskap; Model accuracy; Mutation; Nuclei; Nuclei (cytology); Physiological aspects; Sweden
• ISSN: 1087-0156; 1546-1696; 1546-1696
• DOI: 10.1038/s41587-020-0519-y

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. The location of genetic and epigenetic elements in mammalian nuclei is measured by gradual DNA fragmentation.