The architecture of human chromosomes in interphase nuclei is still largely unknown. Microscopy studies have indicated that specific regions of chromosomes are located in close proximity to the nuclear lamina (NL)1,2,3. This has led to the idea that certain genomic elements may be attached to the NL, which may contribute to the spatial organization of chromosomes inside the nucleus. However, sequences in the human genome that interact with the NL in vivo have not been identified. Here we construct a high-resolution map of the interaction sites of the entire genome with NL components in human fibroblasts. This map shows that genome–lamina interactions occur through more than 1,300 sharply defined large domains 0.1–10 megabases in size. These lamina-associated domains (LADs) are typified by low gene-expression levels, indicating that LADs represent a repressive chromatin environment. The borders of LADs are demarcated by the insulator protein CTCF, by promoters that are oriented away from LADs, or by CpG islands, suggesting possible mechanisms of LAD confinement. Taken together, these results demonstrate that the human genome is divided into large, discrete domains that are units of chromosome organization within the nucleus.
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We thank R. Versteeg, M. Indemans, R. van Driel and O. Giromus for help with FISH; L. Oomen for help with confocal microscopy; A. Bracken and K. Blahnik for data sets; the NKI microarray facility for technical support; E. de Wit for preliminary data analysis; and M. Fornerod, F. van Leeuwen, H.J. Bussemaker, M. van Lohuizen and members of the B.v.S. laboratory for helpful suggestions. This study was supported by the Netherlands Cancer Society, the Netherlands Genomics Initiative, and an European Young Investigator Award to B.v.S. E.B. was supported by NWO Rubicon.
Author Contributions L.G. performed DamID and related experiments; M.B.F. and L.G. performed immunofluorescence microscopy studies; E.B. conducted FISH experiments in the W.d.L. laboratory, with technical support from L.G., B.H.E., A.d.K. and W.T.; L.P. designed microarrays; L.P. and B.v.S. performed data analysis together with L.G.; W.M. and L.W. developed motif and repeat search algorithms. L.G. and B.v.S. conceived and designed the study and wrote the manuscript.
The file contains Supplementary Figures 1-8 and Legends. This file contains a cartoon model summarizing the main results (Supplementary Figure 1) and seven figures showing supporting data and analyses (Supplementary Figures 2-8). (PDF 5445 kb)
The file contains Supplementary Data. This file is a flat text file in GFF format (http://www.sanger.ac.uk/Software/formats/GFF/) listing the positions of all 1,344 LADs (NCBI build 36). Score (column 6) indicates the fraction of array probes inside the LAD with a positive Lamin B1 DamID logratio, after applying a running median filter with window size 5. (TXT 119 kb)
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Guelen, L., Pagie, L., Brasset, E. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453, 948–951 (2008). https://doi.org/10.1038/nature06947
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