HomeWHENWhen Genomic Dna Is Highly Condensed Gene Expression Is Low.

When Genomic Dna Is Highly Condensed Gene Expression Is Low.

The eukaryotic genome is organized into chromatin domains with distinct structure and function. ‘Euchromatin’ is decondensed and capable of gene expression. In contrast, ‘heterochromatin’ is condensed and often transcriptionally silent. Foreign genes inserted in the silent regions are stochastically repressed1,2.

Each chromatin domain is marked up with post-translational histone modifications and histone variants, and such variations in histones play critical roles in the transcriptional regulation of each chromatin region1,2,3,4. In general, euchromatin is rich in hyperacetylated histones and heterochromatin is rich in hypoacetylated histones. In the case of methylation, euchromatin is characterized by methylation of histone H3 at lysine 4 (H3K4me1, H3K4me2 and H3K4me3), whereas heterochromatin is characterized by di- and trimethylation of histone H3 at lysine 9 (H3K9me2 and H3K9me3) and, in higher eukaryotes, trimethylation at lysine 27 (H3K27me3). It is known that some histone methylations associate with gene structures in euchromatin—the trimethylation of histone H3 at lysine 4 (H3K4me3) associates with the promoters, while the trimethylation of histone H3 at lysine 36 (H3K36me3) associates with coding regions4,5.

Studies examining the distribution of histone modifications and DNA-binding proteins suggest that the genomes of Drosophila and humans can be classified into five or more distinct chromatin domains6,7. Despite having accumulated knowledge of chromatin domains at the biochemical level, we know little about the structural organization of chromatin in three-dimensional space. This is because direct observation of small chromatin structures (30-200 nm) has been hindered by the resolution limit of optical microscopes (∼250 nm).

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The simple genome of the fission yeast S. pombe is a useful model for the study of chromatin. Its small genome (∼12.5 Mb) is organized into only three chromosomes and has a gene density of 0.4 genes per kb, and is thus mostly euchromatin. Well-defined regions of heterochromatin are only found at centromeres, telomeres and mating-type regions. S. pombe contains many heterochromatin factors that are conserved in higher eukaryotes, and its nucleosome contains no histone H1 and no known histone H3 variants except for the CENP-A homologue (Cnp1). This makes it one of the simplest model organisms to understand the molecular basis of heterochromatin formation. However, few structural studies have been done of chromatin in S. pombe due to its small nucleus (∼2 μm in diameter).

Recent advances in fluorescence microscopy set the new resolution limit beyond the diffraction limit of the light8, making it possible to directly observe the chromatin structure in S. pombe. We used three-dimensional structured illumination microscopy (3DSIM) that is capable of multicolour, 3D observation at a resolution of 120 and 300 nm in the lateral and vertical directions, respectively9,10. Here we examined the DNA concentration of chromatin domains marked by histone modifications and other factors. We found that silent chromatin regions had the least condensed chromatin in the interphase nucleus of S. pombe. The most condensed region was unexpectedly just next to the subtelomeric silent chromatin, and its condensation is regulated by epigenetic marks at H3K36.

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