Control Of Eukaryotic Gene Expression

Since most eukaryotes are multicellular organisms with many cell types, gene expression must be controlled so that different cell lineages develop differently and remain different. A brain cell is quite different from a liver cell because it contains different proteins even though the DNA in the two cell types is identical. During development and differentiation, different sets of genes are switched on and off. Hemoglobin, for example, is only expressed in developing red blood cells even though the globin genes are present in all types of cell. Genetic engineering technology (Chapter 7) has made the isolation and manipulation of eukaryotic genes possible. This has given us some insight into the extraordinarily complex

processes that regulate transcription of eukaryotic genes and allow a fertilized egg to develop into a multicellular, multitissue adult.

Unlike the situation in bacteria, the eukaryotic cell is divided by the nuclear envelope into nucleus and cytoplasm. Transcription and translation are therefore separated in space and in time. This means that the expression of eukaryotic genes can be regulated at more than one place in the cell. Although gene expression in eukaryotes is controlled primarily by regulating transcription in the nucleus, there are many instances in which expression is controlled at the level of translation in the cytoplasm or by altering the way in which the primary mRNA transcript is processed.

The interaction of RNA polymerase with its promoter is far more complex in eukaryotes than it is in bacteria. This section describes how the transcription of a gene, encoding mRNA, is transcribed by RNA polymerase II. In contrast to bacterial RNA polymerase, RNA polymerase II cannot recognize a promoter sequence. Instead, other proteins known as transcription factors bind to the promoter and guide RNA polymerase II to the beginning of the gene to be transcribed.

The promoter sequence of most eukaryotic genes encoding mRNAs contains an AT-rich region about 25 bp upstream of the transcription start site. This sequence, called the TATA box, binds a protein called the transcription factor IID (TFIID), one of whose subunits is called the TATA-binding protein, or TBP (Fig. 6.14a). Several other transcription factors (TFIIA, TFIIB, TFIIE, TFIIF, and TFIIH) then bind to TFIID and to the promoter region (Fig. 6.14b). TFIIF is the protein that guides RNA polymerase II to the beginning of the gene to be transcribed. The complex formed between the TATA box, TFIID, the other transcription factors, and RNA polymerase is known as the transcription preinitiation complex. Note that the proteins with the prefix TFII are so named because they are iranscription /actors that help RNA polymerase II to bind to promoter sequences.

Although many gene promoters contain a TATA box, some do not. These TATA-less genes usually encode proteins that are needed in every cell and are hence called housekeeping genes. The promoters of these genes contain the sequence GGGGCGGGGC, called the GC box. A protein called Sp1 binds to the GC box and is then able to recruit TATA-binding protein to the DNA even though there is no TATA box for the latter to bind to. TATA-binding protein then recruits the rest of the transcription preinitiation complex so that transcription can proceeed.

In either case, transcription begins when the carboxy-terminal domain of RNA poly-merase II is phosphorylated. This region is rich in the amino acids serine and threonine each of which contains an OH group in their side chain. When these OH groups are phosphorylated (pages 190, 252), RNA polymerase II breaks away from the preinitiation complex and proceeds to transcribe DNA into mRNA (Fig. 6.14c).

Although the formation of the initiation protein complex is sometimes enough to produce a few molecules of RNA, the binding of other proteins to sequences next to the gene greatly increases the rate of transcription producing much more mRNA. These proteins are also called transcription factors, and the DNA sequences to which they bind are called enhancers, so named because their presence enhances transcription. Enhancer sequences often lie upstream of a promoter, but they have also been found downstream. Enhancer sequences and the proteins that bind to them play an important role in determining whether a particular gene is to be transcribed. Some transcription factors bind to a gene to ensure that it is transcribed at the right stage of development or in the right tissue. Figure 6.15 shows how one gene can be transcribed in skeletal muscle but not

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