Locking the genome: nuclear organization and cell fate.

Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
Current opinion in genetics & development (Impact Factor: 8.99). 02/2011; 21(2):167-74. DOI: 10.1016/j.gde.2011.01.023
Source: PubMed

ABSTRACT The differentiation of pluripotent or totipotent cells into various differentiated cell types is accompanied by a restriction of gene expression patterns, alteration in histone and DNA methylation, and changes in the gross nuclear organization of eu- and heterochromatic domains. Several recent studies have coupled genome-wide mapping of histone modifications with changes in gene expression. Other studies have examined changes in the subnuclear positioning of tissue-specific genes upon transcriptional induction or repression. Here we summarize intriguing correlations of the three phenomena, which suggest that in some cases causal relationships may exist.

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    ABSTRACT: A conserved organizational feature of eukaryotic nuclei is the peripheral heterochromatin compartment, which provides a protected area for epigenetically silent genes and gene-poor DNA. In metazoan cells, this compartment is associated with the nuclear lamina, the protein meshwork at the inner edge of the nucleus. Heterochromatin-nuclear lamina interactions promote epigenetic gene silencing, which may drive many normal and diseased biological processes. We recently obtained evidence that a previously unstudied human protein, PRR14, participates in the tethering of heterochromatin to the inner nuclear periphery. PRR14 associates with the nuclear lamina and attaches to heterochromatin through its binding partner, heterochromatin protein 1 (HP1). After disassembly early in mitosis, PRR14 reassembles in two steps, first binding to anaphase chromosomes through HP1, followed by association with the nuclear lamina in telophase. PRR14 may thereby play a role in specifying HP1-bound heterochromatin for reattachment to the nuclear lamina at mitotic exit. Here we review the relevant literature, summarize our initial work, and provide additional comments and findings.
    Nucleus (Austin, Texas) 02/2014; 5(1). · 3.15 Impact Factor
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    ABSTRACT: Abstract Nuclear landscapes were studied during preimplantation development of bovine embryos, generated either by in vitro fertilization (IVF), or generated as cloned embryos by somatic cell nuclear transfer (SCNT) of fetal bovine fibroblasts, using three-dimensional confocal laser scanning microscopy (3D-CLSM) and structured illumination microscopy (3D-SIM). Nuclear landscapes of embryonic nuclei were compared with each other and fibroblast nuclei. We demonstrate that reprogramming of fibroblast nuclei in cloned embryos requires changes of their landscapes similar to nuclei of IVF embryos. On the way towards the 8-cell stage, where major genome activation occurs, a major lacuna, enriched with splicing factors, was formed in the nuclear interior and chromosome territories (CTs) were shifted towards the nuclear periphery. During further development the major lacuna disappeared and CTs were redistributed throughout the nuclear interior forming a contiguous higher order chromatin network. At all stages of development CTs of embryonic and fibroblast nuclei were built up from chromatin domain clusters (CDCs) pervaded by interchromatin compartment (IC) channels. Quantitative analyses revealed a highly significant enrichment of RNA polymerase II and H3K4me3, a marker for transcriptionally competent chromatin, at the periphery of CDCs. In contrast, H3K9me3, a marker for silent chromatin, was enriched in the more compacted interior of CDCs. Despite these striking similarities, we also detected major differences between nuclear landscapes of fibroblasts and cloned embryos. Possible implications of these differences for the developmental potential of cloned animals remain to be investigated. We present a model, which integrates generally applicable structural and functional features of the nuclear landscape.
    Nucleus (Austin, Texas) 11/2014; · 3.15 Impact Factor
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    ABSTRACT: Spatial positioning of genes in the cell nucleus plays an important role in the regulation of genomic functions. Evidence for changes in gene positioning associated with transcriptional activity has been reported. However, our understanding of this phenomenon is still quite limited. We examined how pluripotency genes and hepatocyte-specific genes behave during the differentiation of mouse embryonic stem (ES) cells into hepatocytes, by targeting the loci of the Klf4, Nanog, Oct4, Sox2, Cyp7α1, Pck1, Tat, and Tdo2 genes, and using three-dimensional fluorescence in situ hybridization analyses. We found that each gene has a distinctly inherent localization profile in the ES cell nucleus. During differentiation, the Klf4, Nanog, Oct4, Cyp7α1, Pck1, and Tat loci shifted toward the nuclear center, while the Sox2 and Tdo2 loci shifted toward the periphery. The Klf4, Nanog, Oct4, and Tdo2 seem to prefer the outer regions, rather than the inner regions, when they are active. We also found that the radial positioning of the focused genes in the hepatocyte cell nucleus was highly correlated with the local GC content and the gene density of the surrounding region, but not with gene activity.
    Genetics and molecular research: GMR 01/2014; 13(1):1979-1988. · 0.85 Impact Factor


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May 29, 2014