The Structure of Chromosomes:- Nucleosomes Are Packed into Successively Higher Order Structures
Wrapping of DNA around a nucleosome core compacts the DNA length about sevenfold. The overall compaction in a chromosome, however, is greater than 10,000-fold— ample evidence for even higher orders of structural or ganization. In chromosomes isolated by very gentle methods, nucleosome cores appear to be organized into a structure called the 30 nm fiber (Fig. 1). This packing requires one molecule of histone H1 per nucleosome core. Organization into 30 nm fibers does not ex tend over the entire chromosome but is punctuated by regions bound by sequence-specific (nonhistone) DNA binding proteins. The 30 nm structure also appears to depend on the transcriptional activity of the particular region of DNA. Regions in which genes are being transcribed are apparently in a less-ordered state that contains little, if any, histone H1. The 30 nm fiber, a second level of chromatin or ganization, provides an approximately 100-fold com paction of the DNA. The higher levels of folding are not yet understood, but it appears that certain regions of DNA associate with a nuclear scaffold (Fig. 2). The scaffold-associated regions are separated by loops of DNA with perhaps 20 to 100 kbp. The DNA in a loop may contain a set of related genes. For example, in Drosophila complete sets of histone-coding genes seem to cluster together in loops that are bounded by scaffold attachment sites (Fig. 3). The scaffold itself appears to contain several proteins, notably large amounts of histone H1 (located in the interior of the fiber) and topoisomerase II. The presence of topoisomerase II further emphasizes the relationship between DNA underwinding and chromatin structure. Topoisomerase II is so important to the maintenance of chromatin structure that inhibitors of this enzyme can kill rapidly dividing cells. Several drugs used in cancer chemotherapy are topoisomerase II inhibitors that allow the enzyme to promote strand breakage but not the re sealing of the breaks. Evidence exists for additional layers of organization in eukaryotic chromosomes, each dramatically enhancing the degree of compaction. One model for achieving this compaction is illustrated in Figure 4. Higher order chromatin structure probably varies from chromosome to chromosome, from one region to the next in a single chromosome, and from moment to moment in the life of a cell. No single model can adequately de scribe these structures. Nevertheless, the principle is clear: DNA compaction in eukaryotic chromosomes is likely to involve coils upon coils upon coils.
FIGURE 1 The 30 nm fiber, a higher-order organization of nucleosomes. (a) Schematic illustration of the probable structure of the fiber, showing nucleosome packing. (b) Electron micrograph.
FIGURE 2 A partially unraveled human chromosome, revealing numerous loops of DNA attached to a scaffoldlike structure.
FIGURE 3 Loops of chromosomal DNA attached to a nuclear scaffold. The DNA in the loops is packaged as 30 nm fibers, so the loops are the next level of organization. Loops often contain groups of genes with related functions. Complete sets of histone-coding genes, as shown in this schematic illustration, appear to be clustered in loops of this kind. Unlike most genes, histone genes occur in multiple copies in many eukaryotic genomes.
FIGURE 4 Compaction of DNA in a eukaryotic chromosome. Model for levels of organization that could provide DNA compaction in the chromosomes of eukaryotes. The levels take the form of coils upon coils. In cells, the higher-order structures (above the 30 nm fibers) are unlikely to be as uniform as depicted here.
