Tuesday, December 1, 2009

Packing DNA Beads

The dense packing of DNA in the nucleus of eukaryotes strongly affects how genes within it are expressed, with some regions much more accessible to the transcription machinery than others. At the shortest scales, the accessibility of the DNA double helix is reduced where it is wound around groups of eight histone proteins to form nucleosomes, and the precise position of the nucleosomes in the sequence affects which genes are active.

At a slightly larger scale, the nucleosomes are rather closely packed along the DNA. They can remain floppy, like beads on a string, or they can fold into rods of densely packed beads, which further reduces the accessibility of their DNA. Other proteins in the nucleus, notably the histone H1, help to bind together this dense packing. These rods can pack further, with the help of other proteins.

The histone proteins that form the core of the nucleosome, two copies each of H2A, H2B, H3, and H4, have stray "tails" extending from the core. Small chemical changes at particular positions along these tails can have surprisingly large influence on the expression of the associated DNA. For example, the modification H3K27me3 (three methyl groups attached to the lysine at position 27 on the tail of histone H3) represses expression, while acetylation of the same amino acid, H3K27ac activates expression. There is also a more substantial modification, in which histone H2A is replaced by a variant called H2A.Z also modifies expression.

The detailed mechanisms by which the modifications affect expression, such as changing the wrapping of nucleosomes, the packing of nucleosomes, or recruiting of other proteins in the nucleus, are areas of active research.

Since there are dozens of possible histone tail modifications, there are vast numbers of possible combinations of modifications. Some researchers have proposed that these combinations could each prescribe different expression patterns, for example during development. However, the evidence for a combinatorial "histone code" analogous to the three-base codons of the genetic code remains weak.

Nonetheless, proteins that can modify the tails, either adding or removing a chemical group, can have lasting effects on the activity of the underlying genes. The sirtuin proteins that are candidates for longevity-extending drugs, for example, are best known for their role as histone deacetylases.

Some histone modifications can be passed down through cell division or reproduction, so they qualify as epigenetic changes. In contrast to the natural replication of the mirror-image DNA sequence, replicating histone modifications requires a much more complicated process.

Changes in the pattern of histone modifications are found in many basic biological processes, including development, stem-cell maintenance, and cancer. Particular modification patterns have been used to find specific functional sequences within the DNA, such as transcription start sites and enhancers. For these reasons, the ENCODE project mapped modifications as part of their survey of a select part of the human genome for intense study.

Understanding the mechanisms and roles of DNA organization and how it is changed will be essential to a complete picture of gene regulation.


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