Abstract
The genome is folded into domains located in compartments that are either transcriptionally inert or transcriptionally permissive. Here we used genome-wide strategies to characterize domains during B cell development. Structured interaction matrix analysis showed that occupancy by the architectural protein CTCF was associated mainly with intradomain interactions, whereas sites bound by the histone acetyltransferase p300 or the transcription factors E2A or PU.1 were associated with intra- and interdomain interactions that are developmentally regulated. We identified a spectrum of genes that switched nuclear location during early B cell development. In progenitor cells, the transcriptionally inactive locus encoding early B cell factor (Ebf1) was sequestered at the nuclear lamina, which thereby preserved their multipotency. After development into the pro-B cell stage, Ebf1 and other genes switched compartments to establish new intra- and interdomain interactions associated with a B lineage–specific transcription signature.
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Acknowledgements
We thank G. Hardiman, C. Ludka, L. Edsall, S. Kuan, C. Espinoza, U. Wagner, J. Sprague and Z. Ye for help with Solexa DNA sequencing; J. Dixon for help during the initial phase of Hi-C analysis; B. Wold for suggesting fixation with ethylene glycol bis(succinimidylsuccinate); B. Ren for access to the Illumina Hi-Seq; and members of the Murre laboratory for comments on the manuscript. Supported by the American Recovery and Reinvestment Act (ARRA PHS 3RO1AI082850 to Y.C.L.), the European Molecular Biology Organization (C.Bo.), the Swiss National Science Foundation (C.Bo.), the University of California San Diego, Cancer Center (P30 CA23100) and the US National Institutes of Health (AI082850A and AI00880 to C.K.G. and C.M.).
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R.M. and S.H. contributed equally to this work. Y.C.L., R.M. and S.H. designed and did most of the experiments; S.H. did Gro-Seq analysis; C.Be. did the bioinformatics analysis, analyzed data, suggested new approaches and developed SIMA; M.M., K.M. and V.C. did chromatin immunoprecipitation followed by deep sequencing; C.Bo. provided insight into the topology of the Igk locus; Y.C.L., C.Be. and C.M. wrote the manuscript with contributions from C.K.G., R.M. and S.H.; and C.K.G. and C.M. supervised the study.
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Lin, Y., Benner, C., Mansson, R. et al. Global changes in the nuclear positioning of genes and intra- and interdomain genomic interactions that orchestrate B cell fate. Nat Immunol 13, 1196–1204 (2012). https://doi.org/10.1038/ni.2432
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DOI: https://doi.org/10.1038/ni.2432
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