The complex interplay of transcription factors and polymerases occurs not on naked DNA, but on chromatin. The chromatin structure presents two major problems:

1. How can the transcription factors and initiation complex bind to DNA in the presence of nucleosomes?

Human globin genes - Although present in every human cell, human globin genes are expressed only in the erythroid cells and in a fixed developmental sequence (see here). In embryonic cells that have not yet begun synthesis of any globin, the chromatin of the globin gene cluster appears much the same as in any other cell in the embryo and is quite densely covered with nucleosomes. When differentiation of these cells commits them to globin synthesis, however, the whole globin domain undergoes changes in chromatin structure, including the appearance of regions of DNA particularly susceptible to digestion by nucleases (i.e., not covered by proteins). At the early stages in developing human embryos, these sites appear in the 5' flanking regions of the embryonic genes, which are the first to be transcribed. Later, hypersensitive sites shift to the 5' flanks of the adult genes. Many of these sites represent nucleosome-free regions a few tens or hundreds of base pairs in length. They provide points at which transcription factors and other trans-acting proteins can gain access to promoters and enhancers, thereby allowing the initiation and stimulation of transcription. In the globin genes, it appears that the chromatin structure is rearranged at the time of replication, so as to expose DNA in the relevant portions of chromatin.

Chicken egg white proteins - Another mechanism for exposing DNA regions in chromatin employs protein factors that are able to interfere with chromatin structure at specific loci. For example, transcription of the genes for the chicken egg white proteins ovalbumin, ovomucoid, and lysozyme, is regulated hormonally. Specific hypersensitive sites 5' to some of the egg-white protein genes are opened by the presence of estrogen. Withdrawal of estrogen from an immature chick leads to loss of the hypersensitive sites and an immediate cessation of transcription of the genes. In the hormonal control of transcription, target cells contain specific proteins that bind hormones. When bound to hormone, these proteins are capable of interacting with specific DNA sites or with nonhistone regulatory proteins bound to such sites. Both positive and negative regulation is possible. In some cases, the hormone-binding receptor acts as a positive regulatory factor (for example, by binding to an enhancer element). In others, the hormone-binding receptor can interact with a repressor protein to augment or relieve the repression.

2. How can the actively transcribing polymerase pass through arrays of nucleosomes?

Most genes (with the probable exception of ribosomal genes) carry nucleosomes even when being actively transcribed. Furthermore, the polymerase seems to move quite rapidly along the chromosome. Current evidence favors temporary displacement of nucleosomes during transcription, but the issue is far from settled. One factor that may play a role in such displacement is the development of positive superhelical torsion ahead of a moving polymerase. A polymerase moving along a helical template must either continually rotate about the DNA or build up positive supercoils ahead (overwinding) to compensate for the unwinding it is doing. Such torsion would tend to destabilize nucleosomes, because they contain negatively wrapped DNA.

1. The Role of Chromatin Structure in Transcription

2. The Collaboration of Proteins During Replication

3. Globin Gene Server