Positions of Potential:Nuclear Organization and Gene Expression

Abstract

An elegant study in Drosophila has expanded the evidence that different types of heterochromatin repeats have different characteristics by analyzing a number of randomly inserted transgenes that landed either in telomeric associated sequences on chromosomes 2 and 3, or in the repetitious transposable elements found at the telomere of chromosome 4 (Cryderman et al., 1999xCryderman, D.E., Morris, E.J., Biessmann, H., Elgin, S.C., and Wallrath, L.L. EMBO J. 1999; 18: 3724–3735Crossref | PubMed | Scopus (111)See all References)(Cryderman et al., 1999). As expected, these telomeric transgenes were subject to variegated repression, but they showed different degrees of repression and responded differently to mutations in genes known to affect PEV, namely, suppressor 2 of zeste (Su(z)2) and Su(var)2-5, which encodes HP1, a component of pericentric heterochromatin. Localization of the transgenes within the nucleus by in situ hybridization, showed that the transgenes that are sensitive to HP1 mutations were spatially juxtaposed to centromeric heterochromatin, while those insensitive to HP1 were not. Reciprocal translocations allowed the authors to correlate changes in nuclear position with changes in the strength of the repression. However, the local “heterochromatin” context of the chromosome 2 transgene was dominant over its nuclear position, i.e., the transgene did not respond to changes in HP1 concentrations even when spatially associated with centromeric domains (Cryderman et al., 1999xCryderman, D.E., Morris, E.J., Biessmann, H., Elgin, S.C., and Wallrath, L.L. EMBO J. 1999; 18: 3724–3735Crossref | PubMed | Scopus (111)See all References)(Cryderman et al., 1999). The fact that both local repeat context and position within the nucleus influence the character of gene repression, hints at the diversity that may be possible in mammalian cells, which seem to have numerous variants of repetitive elements. Due to the inherent “stickiness” of repetitive DNA, and its capacity for self-recognition, it is possible that different satellites' repeats will form distinct clusters, each able to offer a unique set of transcription factor recruitment sites. Cell-type specific patterns of gene regulation could then be mediated, at least in part, by a selective sequestering of genes into distinct heterochromatin compartments, which may respond differentially to modifiers of chromatin structure, although they use the same general mechanism of repression (Figure 2)(Figure 2). In view of the data suggesting that it is largely chromatin structure and not active transcription that correlates with a position in the nucleus, it is perhaps more appropriate to propose that relocated genes assume positions of potential, reflecting their potential for repression or expression, due to a position near heterochromatin or distant from it.Figure 2Cell Type–Specific Juxtaposition of Genes to Satellite DNAA hypothetical situation in two differentiated higher eukaryotic cells, each containing three different types of repetitive elements (here arbitrarily labeled SatA, SatB, and SatC). Different promoter-bound complexes (in blue or red, which may contain cell-type specific factors) recruit target genes (X or Z) to the zones of heterochromatin in which they have binding sites, depending on the cell type (compare A and B). Repression is likely to be achieved by a common mechanism involving histone modification and long-range chromatin compaction in both cases. Variations in spatial organization permit many different patterns of repression, making use of both cell type–specific transcription factors and general repressors of active chromatin (indicated as blue, red, or green spots within the heterochromatin)View Large Image | View Hi-Res Image | Download PowerPoint SlideNaturally it is the inheritance of differentiated gene expression patterns that is of primary importance in the development of a complex organism. Thus, there may be need for a system for inheriting three-dimensional order. Since both repetitive DNAs and nuclear localization tend to influence the timing of replication, these pockets of potential repression or expression will tend to be replicated at specific times in S phase. One can speculate that the late replication of genes associated with heterochromatin propagates not only a local chromatin organization, but a tag that maintains its localization within a subnuclear zone (see Cimbora and Groudine [this issue of Cell]). We should remember, however, that the nucleus is not hard wired, and that there is a great deal of movement of both DNA and proteins throughout the cell cycle. Perhaps in addition to the zones of heritable repression established by the Polycomb group genes, the eukaryotic nucleus profits from the tendancy of repetitive, heterochromatic domains to cluster, to set up networks of interactions within the nucleus. It is tempting to speculate that these compartments and their associated genes embody the molecular memory of genetic expression.Cimbora Groudine 2001xCimbora, D.M. and Groudine, M. Cell. 2001; 104: 643–646PubMedSee all ReferencesCimbora Groudine 2001