Recruitment to the Nuclear Periphery Can Alter Expression of Genes in Human Cells

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Abstract
The spatial organisation of the genome in the nucleus has a role in the regulation of gene expression. In vertebrates, chromosomal regions with low gene-density are located close to the nuclear periphery. Correlations have also been made between the transcriptional state of some genes and their location near the nuclear periphery. However, a crucial issue is whether this level of nuclear organisation directly affects gene function, rather than merely reflecting it. To directly investigate whether proximity to the nuclear periphery can influence gene expression in mammalian cells, here we relocate specific human chromosomes to the nuclear periphery by tethering them to a protein of the inner nuclear membrane. We show that this can reversibly suppress the expression of some endogenous human genes located near the tethering sites, and even genes further away. However, the expression of many other genes is not detectably reduced and we show that location at the nuclear periphery is not incompatible with active transcription. The dampening of gene expression around the nuclear periphery is dependent on the activity of histone deacetylases. Our data show that the radial position within the nucleus can influence the expression of some, but not all, genes. This is compatible with the suggestion that re-localisation of genes relative to the peripheral zone of the nucleus could be used by metazoans to modulate the expression of selected genes during development and differentiation. Genes are not randomly arranged in the interphase nucleus. In budding yeast, pathways have been characterised that anchor chromatin at the nuclear periphery, and promote the transcriptional repression of loci positioned there. There are also correlations between inactive chromatin and the nuclear periphery in vertebrates. What has been unclear is whether this is cause or effect. Genes might be inactivated by being positioned close to the nuclear periphery or loci inactivated by other mechanisms might just be sequestered there. In this paper, we provide evidence for a causative role of the nuclear periphery in altering gene expression in human cells. We used the interaction between Eschericia coli lacO operator sequences, inserted into the human genome, and the lac repressor protein, fused to a protein of the inner nuclear membrane, to reposition two different regions of the human genome to the nuclear periphery. The expression of some, but not all, genes on the relocated chromosomes was suppressed. We also show directly that location adjacent to the nuclear periphery is not incompatible with active transcription. Therefore it is possible that positioning of genes relative to the nuclear periphery could be used as a mechanism to modulate gene expression in vertebrates.