Abstract
The regulated expression of genes during development and differentiation is influenced by the availability of regulatory proteins and accessibility of the DNA to the transcriptional apparatus. There is growing evidence that the transcriptional activity of genes is influenced by nuclear organization, which itself changes during differentiation. How do these changes in nuclear organization help to establish specific patterns of gene expression?
Key Points
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During cellular differentiation, only specific subsets of genes are required to carry out a cell's specialized function. The remainder are silenced. Inactive regions of the chromosome are packaged into transcriptionally inactive heterochromatin, mediated by histone deactylation; these regions are unique to each differentiated cell type.
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Gene potentiation is a prerequisite to gene activation. This opens the chromatin structure so that DNA is accessible to the activator proteins required for transcription. Histone acetylation is required to mediate this chromatin opening.
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Chromosomes and genes are organized into specific nuclear zones, termed chromosome territories; within this, potentially active regions are located at the periphery. These territories occupy non-random positions in the interphase nucleus, specific to each cell type. Changes in nuclear architecture are proposed to occur during differentiation.
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Nuclear functions such as transcription also occur in specific compartments of the nucleus. Therefore, nuclear architecture may allow active genes to localize to regions that are permissive for transcription.
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Evidence from Drosophila melanogaster and mammals indicates that positioning of a gene near centromeric heterochromatin often promotes gene silencing; and likewise, that sequestration of a gene into a permissive compartment often allows the stably inherited chromatin opening of a locus.
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Modification of chromatin structure over large regions is proposed to be initiated by assembly of proteins on cis-acting elements called silencer elements. Proteins that bind to these elements include Sir proteins in yeast, and the Polycomb proteins in Drosophila. This repressive structure is proposed to propagate along the chromosome.
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Studies indicate that enhancer elements can counteract these silencing events. Binding of enhancer elements is proposed to recruit the gene to a region in the nucleus that is rich in the transcription factors and histone acetylases required to activate transcription.
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Cancer is associated with disruption of gene expression patterns and global disorganization of chromosome organization within the nucleus.
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Acknowledgements
The authors thank Matthew Lorincz and Bas van Steensel for their useful comments on this manuscript. This work was supported by a special fellowship to C.F. from the Leukemia and Lymphoma Society, a fellowship from the Deutsche Forschungsgemeinschaft to D.S., and NIH grants to M.G.
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Glossary
- HETEROCHROMATIN
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A condensed form of chromatin; the degree of compaction is similar to that of mitotic chromosomes. It is usually found around the centromere.
- INTERPHASE
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The period between two mitotic divisions.
- ENHANCERS
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Increase transcription of a linked promoter if placed in either orientation, upstream or downstream.
- EUCHROMATIN
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Chromatin that appears less compact than mitotic chromosomes. Active genes are contained within euchromatin.
- METHYL-DNA-BINDING DOMAIN PROTEINS
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Proteins that bind specifically to methylated DNA through a methyl-DNA-binding domain. Some of these proteins are involved in transcriptional repression of methylated DNA.
- SATELLITES
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Relatively short DNA sequences that are highly repeated in long tandem arrays.
- CONSTITUTIVE HETEROCHROMATIN
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The fraction of heterochromatin that stays compact through the cell cycle. It is mainly composed of repetitive sequences (satellite DNA; see above), and is concentrated in characteristic regions such as centromeres.
- CHROMOCENTRES
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Aggregates of constitutive heterochromatin from different chromosomes.
- SILENCER ELEMENTS
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Cis-acting elements that are involved in silencing, most probably by directly recruiting repressive proteins.
- LOCUS CONTROL REGION
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Defined by its ability, in transgenic assays, to confer high-level, tissue-specific expression on a linked promoter, at all integration sites.
- FACULTATIVE HETEROCHROMATIN
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Fraction of chromatin that is condensed and inactive in a given cell lineage, which may be decondensed and active in another.
- ANEUPLOIDY
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The ploidy of a cell refers to the number of sets of chromosomes that it contains. Aneuploid karyotypes are those whose chromosome complements are not a simple multiple of the haploid set.
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Francastel, C., Schübeler, D., Martin, D. et al. Nuclear compartmentalization and gene activity. Nat Rev Mol Cell Biol 1, 137–143 (2000). https://doi.org/10.1038/35040083
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DOI: https://doi.org/10.1038/35040083
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