ScienceWeek

GENOME BIOLOGY: ON HETEROCHROMATIN

The following points are made by S.C. Elgin and S.I. Grewal (Current Biology 2003 13:R895):

1) The large genomes of higher eukaryotes suggest a need for stable packaging, particularly as most of the DNA does not code for proteins, and much consists of repetitious sequences, including remnants of invading retrotransposons, transposable elements, and the like. Cytological studies first demonstrated that much of the repetitious DNA is packaged in a condensed form referred to as heterochromatin, and indicated that such packaging limits transcription. During the last few years, remarkable progress has been made in identifying the biochemical characteristics of heterochromatin, suggesting mechanisms by which heterochromatin formation is targeted and maintained.

2) An important characteristic of heterochromatin is that this mode of packaging is epigenetically inherited; i.e. the packaging state is generally maintained after replication and mitosis, independent of the underlying DNA sequence. This implies a biochemical mark and a cellular machinery that can recognize and maintain the mark locally.

3) The DNA of eukaryotic genomes is packaged in nucleosomes, with approximately 167 base pairs (bp) of DNA wrapped in two left-handed turns around a core of eight histones (an [H3+4]2 tetramer and two dimers of [H2A+H2B]). Histone H1 binds to the DNA where the DNA enters and exits from association with the core. "Linker" DNA of approximately 10-50 bp extends to the next histone core. The carboxy-terminal two thirds of the core histones establish the very stable interactions that create the octamer and bind DNA to its surface, whereas the amino-terminal tails are available for interaction with other chromosomal components. The tails are substrates for a number of enzymes that modify specific amino acids of specific histones.

4) While general patterns had been noted, the significance of these histone modifications was first recognized with the demonstration that a particular histone acetyltransferase was the product of a gene previously identified as an activator of gene expression. Heterochromatin is characterized by histone hypoacetylation (in all eukaryotes) and by methylation of histone H3 on lysine 9 in higher eukaryotes, but not in some single-celled eukaryotes such as Saccharomyces. Histone H3 methylated at lysine 9 (H3-mK9) is bound by Heterochromatin Protein 1 (HP1), a highly conserved protein that is directly associated with pericentric heterochromatin.(1-5)

References (abridged):

1. Birchler, J.A., Bhadra, M.P., and Bhadra, U. (2000). Making noise about silence: repression of repeated genes in animals. Curr. Opin. Genet. Dev. 10, 211-216

2. Cohen, D.E. and Lee, J.T. (2002). X-chromosome inactivation and the search for chromosome-wide silencers. Curr. Opin. Genet. Dev. 12, 219-224

3. Dernburg, A.F. and Karpen, G.H. (2002). A chromosome RNAissance. Cell. 111, 159-162

4. Grewal, S.I.S. and Elgin, S.C. (2002). Heterochromatin: new possibilities for inheritance of structure. Curr. Opin. Genet. Dev. 12, 178-187

5. Grewal, S.I. and Moazed, D. (2003). Heterochromatin and epigenetic control of gene expression. Science 301, 798-802

Current Biology http://www.current-biology.com

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MOLECULAR BIOLOGY: ON CHROMATIN FOLDING

The following points are made by P.J. Horn and C.L. Peterson (Science 2002 297:1824):

1) Compaction of eukaryotic genomes into condensed chromatin fibers is required to fit over a meter of DNA within the limited volume of the nucleus; consequently, this compacted structure is inherently repressive to processes that require access to the DNA sequence. The role of higher order chromatin folding in transcriptional control received the lion's share of interest in the early 1980s [e.g., (1,2)], but only recently has this key issue been seriously revisited. Recent advances in our ability to assemble model chromatin in vitro and to identify posttranslational chromatin modifications as key components of gene expression have enhanced interest in the interplay between chromatin structure and transcription. Although substantial strides have been made toward an understanding of basic chromatin structure, much of the detail surrounding "higher order" structure -- chromatin structure beyond the canonical "30-nm" fiber familiar from textbooks -- remains partially or completely uncharacterized.

2) The basic building block of chromatin is the nucleosome, which contains 147 base pairs (bp) of DNA wrapped in a left-handed superhelix 1.7 times around a core histone octamer [two copies each of histones H2A, H2B, H3, and H4 (3)]. Each core histone contains two separate functional domains: a signature "histone-fold" motif sufficient for both histone-histone and histone-DNA contacts within the nucleosome, and NH2-terminal and COOH-terminal "tail" domains that contain sites for posttranslational modifications (such as acetylation, methylation, phosphorylation, and ubiquitination). Although these histone tails are mostly unresolved in the crystal structure of the nucleosome (3), they appear to emanate radially from the nucleosome, conveniently positioned to associate with "linker" DNA residing between nucleosomes or with adjacent nucleosomes (4). In addition to the core histones, metazoan chromatin also contains linker histones (such as histone H1), which bind to nucleosomes and protect an additional ~20 bp of DNA from nuclease digestion at the core particle boundary. Linker histones are not related in sequence to the core histones, but they also contain a globular domain flanked by NH2-terminal and COOH-terminal tail domains (5). Although only the linker histone globular domain is essential for binding to nucleosomes, the tail domains are believed to be important for linker histone roles in chromatin folding.

3) In summary: Eukaryotic genomes are organized into condensed, heterogeneous chromatin fibers throughout much of the cell cycle. Recent studies indicate that even transcriptionally active loci may be encompassed within 80- to 100-nanometer-thick chromonema fibers. These studies suggest that chromatin higher order folding may be a key feature of eukaryotic transcriptional control. There is also evidence suggesting that adenosine-5'-triphosphate-dependent chromatin-remodeling enzymes and histone-modifying enzymes may regulate transcription by controlling the extent and dynamics of chromatin higher order folding.

References (abridged):

1. H. Weintraub, Cell 38, 17 (1984)

2. K. Andersson, B. Bjorkroth, B. Daneholt, J. Cell Biol. 98, 1296 (1984)

3. K. Luger, A. W. Mader, R. K. Richmond, D. F. Sargent, T. J. Richmond, Nature 389, 251 (1997)

4. J. C. Hansen, Annu. Rev. Biophys. Biomol. Struct. 31, 361 (2002)

5. M. H. Parseghian and B. A. Hamkalo, Biochem. Cell Biol. 79, 289 (2001)

Science http://www.sciencemag.org

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