Controlling Transcription

Promoters and Regulatory Sequences Transcription is the process whereby RNA is made from DNA. It is initiated when an enzyme, RNA polymerase, binds to a site on the DNA called a promoter sequence. In most cases, the polymerase is aided by a group of proteins called "transcription factors" that perform specialized functions, such as DNA sequence recognition and regulation of the polymerase's enzyme activity. Other regulatory sequences include activators, repressors, and enhancers. These sequences can be cis-acting (affecting genes that are adjacent to the sequence) or trans-acting (affecting expression of the gene from a distant site), even on another chromosome.

The Globin Genes: An Example of Transcriptional Regulation An example of transcriptional control occurs in the family of genes responsible for the production of globin. Globin is the protein that complexes with the iron-containing heme molecule to make hemoglobin. Hemoglobin transports oxygen to our tissues via red blood cells. In the adult, red blood cells do not contain DNA for making new globin; they are ready-made with all of the hemoglobin they will need. During the first few weeks of life, embryonic globin is expressed in the yolk sac of the egg. By week five of gestation, globin is expressed in early liver cells. By birth, red blood cells are being produced, and globin is expressed in the bone marrow. Yet, the globin found in the yolk is not produced from the same gene as is the globin found in the liver or bone marrow stem cells. In fact, at each stage of development, different globin genes are turned on and off through a process of transcriptional regulation called "switching". To further complicate matters, globin is made from two different protein chains: an alpha-like chain coded for on chromosome 16; and a beta-like chain coded for on chromosome 11. Each chromosome has the embryonic, fetal, and adult form lined up on the chromosome in a sequential order for developmental expression. The developmentally regulated transcription of globin is controlled by a number of cis-acting DNA sequences, and although there remains a lot to be learned about the interaction of these sequences, one known control sequence is an enhancer called the Locus Control Region (LCR). The LCR sits far upstream on the sequence and controls the alpha genes on chromosome 16. It may also interact with other factors to determine which alpha gene is turned on. Thalassemias are a group of diseases characterized by the absence or decreased production of normal globin, and thus hemoglobin, leading to decreased oxygen in the system. There are alpha and beta thalassemias, defined by the defective gene, and there are variations of each of these, depending on whether the embryonic, fetal, or adult forms are affected and/or expressed. Although there is no known cure for the thalassemias, there are medical treatments that have been developed based on our current understanding of both gene regulation and cell differentiation. Treatments include blood transfusions, iron chelators, and bone marrow transplants. With continuing research in the areas of gene regulation and cell differentiation, new and more effective treatments may soon be on the horizon, such as the advent of gene transfer therapies.