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

By L. Finlan, D. Sproul, I. Thomson, S. Boyle, Elizabeth Kerr, P. Perry, Bauke Ylstra, Jonathan R. Chubb, Wendy A. Bickmore. PLoS Genetics, 2008

607 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/709a102192b332f3f016bb195fc7560145267921

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Citations in the corpus

Chromosome territories. (2010, background): “They found that some genes were suppressed when closely associated with the envelope, but that others were not (Finlan et al. 2008; Kumaran and Spector 2008; Reddy et al. 2008).”
Single-Cell and Single-Molecule Analysis of Gene Expression Regulation (2016, background): “Relocation of a specific human chromosome to the nuclear periphery reduces the expression levels of some endogenous human genes located near the tethering sites (51).”
The Major Architects of Chromatin: Architectural Proteins in Bacteria, Archaea and Eukaryotes (2008, background): “This suggests a scenario in which BAF tethers chromatin to the nuclear lamina, which has been suggested as a mechanism to down-regulate the expression of genes (Finlan et al., 2008).”
Functional and mechanistic diversity of distal transcription enhancers (2011, positive): “For example, artificial tethering of reporter genes to the nuclear lamina or nuclear periphery has been shown to result in downregulation of the reporter and of neighboring genes, although not all genes are affected (Andrulis et al., 1998; Finlan et al., 2008; Reddy et al., 2008).”
A three-dimensional map of the human genome at kilobase resolution reveals principles of chromatin looping (2014, positive): “This observation is consistent with microscopy studies associating changes in gene expression with changes in nuclear localization (Finlan et al., 2008).”
Single-cell dynamics of genome-nuclear lamina interactions. (2013, positive): “Contact of a LAD with the NL may help to repress the genes within this LAD, which is consistent with studies showing that artificial anchoring of genes to the NL can lead to reduced transcriptional activity (Dialynas et al., 2010; Finlan et al., 2008; Reddy et al., 2008).”
LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. (2013, background): “In mammalian cells, targeting chromatin to the NE mediates its silencing in a histone-deacetylation-dependent manner (Finlan et al., 2008), which concurs with HDAC3 associating with LEM domain proteins.”
A decade of 3C technologies: insights into nuclear organization. (2012, background): “Targeting specific factors to these arrays can sometimes—but not always—induce repositioning, as was seen for lamin-associated proteins that can direct loci to the nuclear periphery (Finlan et al. 2008; Kumaran and Spector 2008; Reddy et al. 2008).”
Charting histone modifications and the functional organization of mammalian genomes (2011, background): “Remarkably, tethering experiments show that interaction with the nuclear lamina is not only correlative but is also causal in reducing gene expressio”
Molecular maps of the reorganization of genome – nuclear lamina interactions during differentiation (2010, background): “Tethering of genes to the NL can, at least in certain genomic contexts, lead to reduced gene expression (Finlan et al., 2008; Kumaran and Spector, 2008; Reddy et al., 2008), and depletion of Lamin B in Drosophila causes activation of a gene cluster that is normally silent and located at the NL…”
Nuclear architecture of rod photoreceptor cells adapts to vision in mammalian evolution. (2009, background): “Genes normally transcribed in the nuclear interior may remain active after experimental anchoring to the nuclear periphery (Finlan et al., 2008; Kumaran and Spector, 2008), while disruption of the tethering to the nuclear periphery may be insufficient for transcriptional activation (Gartenberg et al”