Genetic regulation, or regulation of gene expression, covers the entire process from transcription of the genetic code in the nucleus to the formation of proteins in the cytoplasm. Regulation of gene expression provides all living organisms with the ability to respond to changes in their environment. In animals that have many different types of cells, tissues, and organs, differential regulation of gene expression also permits the many different cell types in the body to each perform their specialized functions. Although a cardiac myocyte contains the same genetic code as a renal tubular epithelia cell, many genes are expressed in cardiac cells that are not expressed in renal tubular cells. The ultimate measure of gene “expression” is whether (and how much) of the gene products (proteins) are produced because proteins carry out cell functions specified by the genes. Regulation of gene expression can occur at any point in the pathways of transcription, RNA processing, and translation.
The Promoter Controls Gene Expression. Synthesis of cellular proteins is a complex process that starts with the transcription of DNA into RNA. The transcription of DNA is controlled by regulatory elements found in the promoter of a gene (Figure1). In eukaryotes, which includes all mammals, the basal promoter consists of a sequence of seven bases (TATAAAA) called the TATA box, the binding site for the TATA-binding protein and several other important transcription factors that are collectively referred to as the transcription factor IID complex. In addition to the transcription factor IID complex, this region is where transcription factor IIB binds to both the DNA and RNA polymerase 2 to facilitate transcription of the DNA into RNA. This basal promoter is found in all protein-coding genes, and the polymerase must bind with this basal promoter before it can begin traveling along the DNA strand to synthesize RNA. The upstream promoter is located farther upstream from the transcription start site and contains several binding sites for positive or negative transcription factors that can affect transcription through interactions with proteins bound to the basal promoter. The structure and transcription factor binding sites in the upstream promoter vary from gene to gene to give rise to the different expression patterns of genes in different tissues.
Fig1. Gene transcription in eukaryotic cells. A complex arrangement of multiple clustered enhancer modules is interspersed with insulator elements, which can be located either upstream or downstream of a basal promoter containing TATA box (TATA), proximal promoter elements (response elements, RE), and initiator sequences (INR).
Transcription of genes in eukaryotes is also influenced by enhancers, which are regions of DNA that can bind transcription factors. Enhancers can be located a great distance from the gene they act on or even on a different chromosome. They can also be located either upstream or downstream of the gene that they regulate. Although enhancers may be located far away from their target gene, they may be relatively close when DNA is coiled in the nucleus. It is estimated that there are 110,000 gene enhancer sequences in the human genome.
In the organization of the chromosome, it is important to separate active genes that are being transcribed from genes that are repressed. This separation can be challenging because multiple genes may be located close together on the chromosome. This separation is achieved by chromosomal insulators. These insulators are gene sequences that provide a barrier so that a specific gene is isolated against transcriptional influences from surrounding genes. Insulators can vary greatly in their DNA sequence and the proteins that bind to them. One way an insulator activity can be modulated is by DNA methylation, which is the case for the mammalian insulin-like growth factor 2 (IGF-2) gene. The mother’s allele has an insulator between the enhancer and promoter of the gene that allows for the binding of a transcriptional repressor. However, the paternal DNA sequence is methylated such that the transcriptional repressor cannot bind to the insulator and the IGF-2 gene is expressed from the paternal copy of the gene.
Other Mechanisms for Control of Transcription by the Promoter. Variations in the basic mechanism for control of the promoter have been rapidly discovered in the past 2 decades. Without giving details, let us list some of them:
1. A promoter is frequently controlled by transcription factors located elsewhere in the genome. That is, the regulatory gene causes the formation of a regulatory protein that in turn acts either as an activator or a repressor of transcription.
2. Occasionally, many different promoters are con trolled at the same time by the same regulatory protein. In some instances, the same regulatory protein functions as an activator for one promoter and as a repressor for another promoter.
3. Some proteins are controlled not at the starting point of transcription on the DNA strand but farther along the strand. Sometimes the control is not even at the DNA strand itself but during the processing of the RNA molecules in the nucleus before they are released into the cytoplasm; control may also occur at the level of protein formation in the cytoplasm during RNA translation by the ribosomes.
4. In nucleated cells, the nuclear DNA is packaged in specific structural units, the chromosomes. Within each chromosome, the DNA is wound around small proteins called histones, which in turn are held tightly together in a compacted state by still other proteins. As long as the DNA is in this compacted state, it cannot function to form RNA. However, multiple control mechanisms are being discovered that can cause selected areas of chromosomes to become decompacted one part at a time so that partial RNA transcription can occur. Even then, specific transcriptor factors control the actual rate of transcription by the promoter in the chromosome. Thus, still higher orders of control are used to establish proper cell function. In addition, signals from outside the cell, such as some of the body’s hormones, can activate specific chromosomal areas and specific transcription factors, thus controlling the chemical machinery for function of the cell.
Because there are more than 30,000 different genes in each human cell, the large number of ways in which genetic activity can be controlled is not surprising. The gene control systems are especially important for controlling intracellular concentrations of amino acids, amino acid derivatives, and intermediate substrates and products of carbohydrate, lipid, and protein metabolism.
