Three-dimensional genome structures of single diploid human cells

• Published in: Science (American Association for the Advancement of Science) Vol. 361; no. 6405; pp. 924 - 928
• Main Authors: Tan, Longzhi, Xing, Dong, Chang, Chi-Han, Li, Heng, Xie, X Sunney
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 31.08.2018
• Subjects: Algorithms; Alleles; Amplification; Blood cells; Blood Cells - chemistry; Blood Cells - ultrastructure; Cell Line, Tumor; Cell Nucleus - genetics; Cell Nucleus - ultrastructure; Chromatin; Chromatin - chemistry; Chromatin - genetics; Chromatin - ultrastructure; Chromosomes; Chromosomes, Human, X - ultrastructure; Conformation; Copy number; Dependence; Diploidy; DNA - chemistry; DNA - ultrastructure; DNA Copy Number Variations; Gene expression; Gene Expression Regulation; Gene regulation; Genome, Human; Genomes; Genomic Imprinting; Haplotypes; Humans; Imaging, Three-Dimensional - methods; Literary Devices; Nucleic Acid Amplification Techniques; Nucleic Acid Conformation; Nucleotide sequence; Protein Conformation; Single-Cell Analysis - methods; Spatial discrimination; Spatial resolution; Structural analysis; Typing
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aat5641

Three-dimensional genome structures play a key role in gene regulation and cell functions. Characterization of genome structures necessitates single-cell measurements. This has been achieved for haploid cells but has remained a challenge for diploid cells. We developed a single-cell chromatin conformation capture method, termed Dip-C, that combines a transposon-based whole-genome amplification method to detect many chromatin contacts, called META (multiplex end-tagging amplification), and an algorithm to impute the two chromosome haplotypes linked by each contact. We reconstructed the genome structures of single diploid human cells from a lymphoblastoid cell line and from primary blood cells with high spatial resolution, locating specific single-nucleotide and copy number variations in the nucleus. The two alleles of imprinted loci and the two X chromosomes were structurally different. Cells of different types displayed statistically distinct genome structures. Such structural cell typing is crucial for understanding cell functions.