Generally, every cell of an individual metazoan organism contains the same genetic information. Thus, the differences between cell types within an organism must be explained by differential expression of the common genetic information. Chromatin containing active genes (ie, transcriptionally or potentially transcriptionally active chromatin) has been shown to differ in several important ways from that of inactive regions. The nucleosome structure of active chromatin appears to be altered, sometimes quite extensively, in highly active regions. DNA in active chromatin contains large regions (about 100,000 bases long) that are relatively more sensitive to digestion by a nuclease such as DNase I. DNase I makes single-strand cuts in nearly any segment of DNA due to its low-sequence specificity. However, DNase I will only avidly digest DNA that is not protected, or bound by protein. The sensitivity to DNase I of active chromatin regions reflects only a potential for transcription rather than transcription itself, and in several different cellular systems can be correlated with a relative lack of 5-methyldeoxycytidine (meC; see Figure 1) in the DNA, and particular histone variants and/or histone PTMs (phosphorylation, acetylation, etc.; see Table 1).

Fig1. Four uncommon naturally occurring pyrimidines and purines.

Table1. Possible Roles of Posttranslationally Modified Histones

Within the large regions of active chromatin there exist shorter stretches of 100 to 300 nucleotides that exhibit an even greater (another 10-fold) sensitivity to DNase I. These hyper sensitive sites probably result from a structural conformation that favors access of the nuclease to the DNA. These regions are often located immediately upstream from the active gene and are the location of interrupted nucleosomal structure caused by the binding of nonhistone regulatory transcription factor proteins (enhancer-binding transcriptional activator proteins). In many cases, it seems that if a gene is capable of being transcribed, it very often has a DNase hypersensitive site(s) in the chromatin immediately upstream. As noted earlier, nonhistone regulatory proteins involved in transcription control and those involved in maintaining access to the template strand lead to the formation of hypersensitive sites. Such sites often provide the first clue about the presence and location of a transcription control element.

By contrast, transcriptionally inactive chromatin is densely packed during interphase as observed by electron microscopic studies and is referred to as heterochromatin; transcription ally active chromatin stains less densely and is referred to as euchromatin. Generally, euchromatin is replicated earlier than heterochromatin in the mammalian cell cycle (see following discussion). The chromatin in these regions of inactivity is often high in meC content, and histones therein contain relatively lower levels of certain “activating” covalent modifications and higher levels of “repressing” histone PTMs (see Table 1).

There are two types of heterochromatin: constitutive and facultative. Constitutive heterochromatin is always relatively highly condensed (ie, heterochromatic), and thus essentially always inactive. Such constitutive heterochromatin is found in the regions near the chromosomal centromere and at chromosomal ends (telomeres). Facultative heterochromatin is at times condensed, but at other times it is actively transcribed and, thus, uncondensed and appears as euchromatin. Of the two members of the X-chromosome pair in mammalian females, one X chromosome is almost completely inactive transcriptionally and is heterochromatic. However, the heterochromatic X chromosome decondenses during gametogenesis and becomes transcriptionally active during early embryogenesis—thus, it is facultative heterochromatin.

Certain cells of insects, for example, Chironomus and Drosophila, contain giant chromosomes that have been replicated for multiple cycles without separation of daughter chromatids. These copies of DNA line up side by side in precise register and produce a banded chromosome containing regions of condensed chromatin and lighter bands of more extended chromatin. Transcriptionally active regions of these polytene chromosomes are especially decondensed into “puffs” that can be shown to contain the enzymes responsible for transcription and to be the sites of RNA synthesis (Figure 2). Using highly sensitive fluorescently labeled hybridization probes, specific gene sequences can be mapped, or “painted,” within the nuclei of human cells, even without polytene chromosome formation, using fluorescence in situ hybridization, or FISH techniques.

Fig2. Illustration of the tight correlation between the presence of RNA polymerase II and messenger RNA synthesis. A number of genes, labeled A, B (top), and 5C, but not genes at locus (band) BR3 (5C, BR3, bottom) are activated when midge fly Chironomus tentans larvae are subjected to heat shock (39°C for 30 minutes). (A) Distribution of RNA polymerase II in isolated chromosome IV from the salivary gland (groups of light spotsat arrows). The enzyme was detected by immunofluorescence using a fluorescently labeled antibody directed against the polymerase. The 5C and BR3 are specific bands of chromosome IV, and the arrows indicate puffs (ie, A, B, 5C). (B) Autoradiogram of a chromosome IV that was incubated in 3H-uridine to label the RNA. Note the correspondence of the immunofluorescence and presence of the radioactive RNA (black dots) (ie, A, B, 5C). Bar = 7 μm. (Reproduced with permission from Sass H. RNA polymerase B in polytene chromosomes: immunofluorescent and autoradiographic analysis during stimulated and repressed RNA synthesis. Cell. 1982;28(2):269-278.)

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مواضيع ذات صلة

The Exact Function of Much of the Mammalian Genome is Not Well Understood

DNA is organized into Chromosomes

The Nucleosome Contains Histone & DNA

Histones Are the Most Abundant Chromatin Proteins

Specific Nucleases Digest Nucleic Acids

Directions for Future Research in Molecular Biology

The ras-fos-jun Pathway

Recessive Oncogenic Mutations, Tumor Suppressors

Small RNA

Ribosomal RNA

Messenger RNA

Identification of the src and sis Gene