Abstract
Genomic information is selectively used to direct spatial and temporal gene expression during differentiation. Interactions between topologically associating domains (TADs) and between chromatin and the nuclear lamina organize and position chromosomes in the nucleus. However, how these genomic organizers together shape genome architecture is unclear. Here, using a dual-lineage differentiation system, we report long-range TAD–TAD interactions that form constitutive and variable TAD cliques. A differentiation-coupled relationship between TAD cliques and lamina-associated domains suggests that TAD cliques stabilize heterochromatin at the nuclear periphery. We also provide evidence of dynamic TAD cliques during mouse embryonic stem-cell differentiation and somatic cell reprogramming and of inter-TAD associations in single-cell high-resolution chromosome conformation capture (Hi-C) data. TAD cliques represent a level of four-dimensional genome conformation that reinforces the silencing of repressed developmental genes.
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Data availability
Hi-C, RNA-seq, lamin B1 ChIP–seq and H3K9me3 ChIP–seq data generated during this study are available at NCBI GEO under accession number GSE109924 without any restrictions. ChIP-seq data were downloaded from Roadmap Epigenomics55 (datasets E023 and E025; H3K4me3, H3K9me3, H3K27me3 and H3K36me3) and from NCBI GEO GSE20752 (CTCF)56. Hi-C data for the differentiation of mouse ES cells were downloaded from NCBI GEO GSE96107. Hi-C data for mouse B cell reprogramming were downloaded from NCBI GEO GSE96611. RNA-sequencing data for adipose differentiation26 were downloaded from NCBI GEO GSE60237. Mouse consensus LAD data36 were downloaded from NCBI GEO GSE17051. LOCK data32 were downloaded from NCBI GEO GSE71809. Figures with the associated raw data cited here are Figs. 1–6 and Supplementary Figs. 1–5 and 7–11.
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Acknowledgements
We thank K. Vekterud and A. Sørensen for expert technical assistance. We thank the Genomics Core Facility of Oslo University Hospital and the Biomolecular Resource Facility at the John Curtin School of Medical Research, The Australian National University, for sequencing services. This work was supported by the National Health and Medical Research Council (no. 1104340 to D.T.), EU Scientia Fellowship FP7-PEOPLE-2013-COFUND (no. 609020 to M.-O.B.), the Research Council of Norway (no. 249734 to P.C.), The Norwegian Cancer Society (no. 6822903 to E.D. and no. 190299-2017 to P.C.) and South-East Health Norway (no. 2018082 to P.C.).
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J.P. and P.C. designed the study; J.P., T.M.L.A., D.T. and P.C. wrote the manuscript; J.P., T.M.L.A. and S.K. did bioinformatics analyses; E.D. analyzed FISH data and wrote methods; M.N. and M.-O.B. did Hi-C and ChIP experiments; D.T. and P.C. supervised the work.
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Supplementary Information
Supplementary Figures 1–11
Supplementary Table 1
Statistics for indicated figures.
Supplementary Table 2
Gene ontology terms enriched for genes in dynamic TAD cliques during adipose differentiation.
Supplementary Table 3
Gene ontology terms enriched for genes in cliques and not in cliques, which are downregulated during adipose differentiation.
Supplementary Table 4
FISH probe information.
Supplementary Table 5
Genes contained in adipose- and neuronalspecific TAD cliques on D3 of differentiation.
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Paulsen, J., Liyakat Ali, T.M., Nekrasov, M. et al. Long-range interactions between topologically associating domains shape the four-dimensional genome during differentiation. Nat Genet 51, 835–843 (2019). https://doi.org/10.1038/s41588-019-0392-0
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DOI: https://doi.org/10.1038/s41588-019-0392-0
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