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Transcriptional repression mediated by repositioning of genes to the nuclear lamina

Nature volume 452, pages 243–247 (2008)Cite this article

Abstract

Nuclear compartmentalization seems to have an important role in regulating metazoan genes1,2. Although studies on immunoglobulin and other loci have shown a correlation between positioning at the nuclear lamina and gene repression, the functional consequences of this compartmentalization remain untested2,3. We devised an approach for inducible tethering of genes to the inner nuclear membrane (INM), and tested the consequences of such repositioning on gene activity in mouse fibroblasts. Here, using three-dimensional DNA-immunoFISH, we demonstrate repositioning of chromosomal regions to the nuclear lamina that is dependent on breakdown and reformation of the nuclear envelope during mitosis. Moreover, tethering leads to the accumulation of lamin and INM proteins, but not to association with pericentromeric heterochromatin or nuclear pore complexes. Recruitment of genes to the INM can result in their transcriptional repression. Finally, we use targeted adenine methylation (DamID) to show that, as is the case for our model system, inactive immunoglobulin loci at the nuclear periphery are contacted by INM and lamina proteins. We propose that these molecular interactions may be used to compartmentalize and to limit the accessibility of immunoglobulin loci to transcription and recombination factors.

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Figure 1: Quantitative analysis of tethered loci by 3D DNA-immunoFISH.
Figure 2: Lamin B, EMD and LAP2, but not NPCs, accumulate at sites of tethered foci.
Figure 3: Tethering leads to transcriptional repression and histone deacetylation of genes at site of attachment to the INM.
Figure 4: Inactive immunoglobulin heavy chain loci that are positioned at the nuclear periphery contact the nuclear lamina.

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Gene Expression Omnibus

Data deposits

The microarray data can be found at the Gene Expression Omnibus at NCBI (http://www.ncbi.nlm.nih.gov/projects/geo/) under accession number GSE10176.

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Acknowledgements

We thank A. Belmont for the lacO and GFP-LacI plasmids and K. Van Steensel for DamID plasmids. We are grateful to members of the laboratory for critical input and support by the Howard Hughes Medical Institute. J.M.Z. is supported by an NIH training grant.

Author Contributions K.L.R. designed and performed most of the experiments. J.M.Z. carried out the DamID experiments with K.L.R.. E.B. contributed the microarray analysis. K.L.R. and H.S. wrote the manuscript.

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Authors and Affiliations

  1. Howard Hughes Medical Institute,,

    K. L. Reddy, J. M. Zullo & H. Singh

  2. Department of Molecular Genetics and Cell Biology, The University of Chicago, GCIS W522, 929 East 57th Street, Chicago, Illinois 60637, USA,

    K. L. Reddy, J. M. Zullo, E. Bertolino & H. Singh

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  1. K. L. Reddy
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Correspondence to H. Singh.

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Reddy, K., Zullo, J., Bertolino, E. et al. Transcriptional repression mediated by repositioning of genes to the nuclear lamina. Nature 452, 243–247 (2008). https://doi.org/10.1038/nature06727

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