Chemistry of Life

Molecular genetics, biochemistry


Nucleosomes are chromosomal structures in which DNA is wrapped around histone proteins – this composite material is termed chromatin. Nucleosomes compact the DNA and render it inaccessible and hence inactive because transcription factors can only bind to naked DNA (euchromatin). Nucleosomes are mobile, enabling euchromatin (unwound facultative heterochromatin) to be expressed (actively transcribed into RNA for ultimate translation into polypeptide and protein molecules). The structure of histone proteins is highly conserved. Each human cell contains about 30 million nucleosomes.

While the genetic code determines the production of proteins, a 'second code' may determine the structural location of nucleosomes. The new code is described in the July '06 issue of Nature by Eran Segal and colleagues.

"Biologists have suspected for years that some positions on the DNA, notably those where it bends most easily, might be more favorable for nucleosomes than others, but no overall pattern was apparent. Drs. Segal and Widom analyzed the sequence at some 200 sites in the yeast genome where nucleosomes are known to bind, and discovered that there is indeed a hidden pattern . . . The pattern is a combination of sequences that makes it easier for the DNA to bend itself and wrap tightly around a nucleosome. But the pattern requires only some of the sequences to be present in each nucleosome binding site, so it is not obvious." [NYT].

Abstract linked: A genomic code for nucleosome positioning.
Eukaryotic genomes are packaged into nucleosome particles that occlude the DNA from interacting with most DNA binding proteins. Nucleosomes have higher affinity for particular DNA sequences, reflecting the ability of the sequence to bend sharply, as required by the nucleosome structure. However, it is not known whether these sequence preferences have a significant influence on nucleosome position in vivo, and thus regulate the access of other proteins to DNA. Here we isolated nucleosome-bound sequences at high resolution from yeast and used these sequences in a new computational approach to construct and validate experimentally a nucleosome-DNA interaction model, and to predict the genome-wide organization of nucleosomes. Our results demonstrate that genomes encode an intrinsic nucleosome organization and that this intrinsic organization can explain approximately 50% of the in vivo nucleosome positions. This nucleosome positioning code may facilitate specific chromosome functions including transcription factor binding, transcription initiation, and even remodelling of the nucleosomes themselves.
Segal E, Fondufe-Mittendorf Y, Chen L, Thastrom A, Field Y, Moore IK, Wang JP, Widom J. A genomic code for nucleosome positioning. Nature. 2006 Jul 19; [Epub ahead of print]

Changing the DNA landscape: putting a SPN on chromatin. [Curr Top Microbiol Immunol. 2003] PMID: 12596908
Specific local histone-DNA sequence contacts facilitate high-affinity, non-cooperative nucleosome binding of both adf-1 and GAGA factor. [Nucleic Acids Res. 1998] PMID: 9826764
New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning. [J Mol Biol. 1998] PMID: 9514715
Heat shock factor can activate transcription while bound to nucleosomal DNA in Saccharomyces cerevisiae. [Mol Cell Biol. 1994] PMID: 8264586
Nucleosome packaging and nucleosome positioning of genomic DNA. [Proc Natl Acad Sci U S A. 1997] PMID: 9037027
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The nucleosome is the basic repeat element of chromatin, and consists of 147 base pairs (bp) of DNA wrapped 1.7 times around an octamer of histone proteins (two copies each of the core histones H2A, H2B, H3, and H4).

Nucleosomes are connected by about 20 to 60 bp of linker DNA to form the 10-nm "beads-on-a-string" array. This can be further compacted into a "30-nm" chromatin fiber.

Two classes of model for chromatin have been proposed: (a) the "one-start helix" in which nucleosomes, connected by bent linker DNA, are arranged linearly in a higher order helix; or (b) the "two-start helix" in which nucleosomes, connected by straight linker DNA, zigzag back and forth between two adjacent helical stacks.

To distinguish between these two competing models of higher order chromatin folding, Dorigo and co-workers employed a fully defined in vitro system to generate regular nucleosomal arrays. Analysis of the length of the nucleosome stacks, now connected only by internucleosomal cross-links, revealed a two-start rather than a one-start organization. This interpretation was corroborated by electron microscopy. Thus, local interactions between nucleosomes can drive self-organization into a higher order chromatin fiber. Adapted from: Adone Mohd-Sarip and C. Peter Verrijzer (Science 2004 306:1484) PubMed Mohd-Sarip A, Verrijzer CP. Molecular biology. A higher order of silence. Science. 2004 Nov 26;306(5701):1484-5.
Comment on: Science. 2004 Nov 26;306(5701):1571-3. & Science. 2004 Nov 26;306(5701):1574-7.

Chromatin compaction by a polycomb group protein complex. [Science. 2004] PMID: 15567868
Nucleosome arrays reveal the two-start organization of the chromatin fiber. [Science. 2004] PMID: 15567867
Molecular biology. Chromatin higher order folding--wrapping up transcription. [Science. 2002] PMID: 12228709
Introduction: assembly, remodeling and modification of chromatin. [Cell Mol Life Sci. 2001] PMID: 11437227
H2A.Z alters the nucleosome surface to promote HP1alpha-mediated chromatin fiber folding. [Mol Cell. 2004] PMID: 15546624
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Nucleosome packaging and nucleosome positioning of genomic DNA.
The goals of this study were to assess the extent to which bulk genomic DNA sequences contribute to their own packaging in nucleosomes and to reveal the relationship between nucleosome packaging and positioning. Using a competitive nucleosome reconstitution assay, we found that at least 95% of bulk DNA sequences have an affinity for histone octamer in nucleosomes that is similar to that of randomly synthesized DNA; they contribute little to their own packaging at the level of individual nucleosomes. An equation was developed that relates the measured free energy to the fractional occupancy of specific nucleosome positions. Evidently, the bulk of eukaryotic genomic DNA is also not evolved or constrained for significant sequence-directed nucleosome positioning at the level of individual nucleosomes. Implications for gene regulation in vivo are discussed. Lowary PT, Widom J. Nucleosome packaging and nucleosome positioning of genomic DNA. (Free Full Text Article) Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1183-8.

New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning. [J Mol Biol. 1998] PMID: 9514715
Artificial nucleosome positioning sequences. [Proc Natl Acad Sci U S A. 1989] PMID: 2798415
DNA sequence-dependent contributions of core histone tails to nucleosome stability: differential effects of acetylation and proteolytic tail removal. [Biochemistry. 2000] PMID: 10736184
Archaeal histone selection of nucleosome positioning sequences and the procaryotic origin of histone-dependent genome evolution. [J Mol Biol. 2000] PMID: 11021967
Two DNA-binding sites on the globular domain of histone H5 are required for binding to both bulk and 5 S reconstituted nucleosomes. [J Mol Biol. 2000] PMID: 11071807
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. . . transcription begun 10/06/06