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GENE REGULATION IN HIGHER ORGANSIMS Although eukaryotes do not have operons and are much more difficult to study experimentally, examples of gene regulation and knowledge of the molecular mechanisms involved are coming to light. Although eukaryotic regulation is relatively more complex, many of the principles from the lac-operon can be applied. For example, a number of promoters that allow tissue specific expression thorough interaction with trans-acting factors have been defined. One quite useful application in plants has been the ability to place structural genes under the control of seedspecific promoters so that the protein can be made and stored in seeds. The local company Prodigene www.prodigene.com is a pioneer in this research, and is now selling corn that contains a valuable protein called avidin that is widely used in basic biology research. A bushel of corn can provide as much avidin as would normally be isolated from a boxcar full of eggs, the usual source of this protein. Even better, the corn can be stored without spoiling and the avidin can still be isolated in active form! Lets look at a few examples from humans where gene regulation can be seen to occur, even if all the molecular details are not available. One interesting example involves the same enzyme that we called β galactosidase in bacteria. In humans, the enzyme is simply called lactase. Since human milk is 7% lactose, it is fortunate that almost all babies are born with lactase. On aging however, many adults lose the ability to digest lactose; they become lactose intolerant. If these individuals consume lactose, they tend to develop gas, cramps and even diarrhea. the ability of adults to digest lactose is culture-dependent. In general, in dairy-oriented cultures adults maintain lactase, whereas in non-dairy cultures they do not. For example, among Finns and Swedes 96 % of the adults are lactose tolerant, while among Eskimos and Asians, 88-98 % of adults are intolerant. Adults in seemingly dairy-oriented cultures where the lactose is pre-digested by microbes to make cheese or yogurt also tend to be intolerant. It is not clear if synthesis of the enzyme is shut down as a consequence on non-exposure to milk, or simply as a function of aging. It does not appear to be easy to turn the lactase gene back on once it has been shut off. A clear case of developmental regulation can be seen in our genes for hemoglobin; the molecule in red blood cells that function to transport oxygen. All hemoglobins are made of four polypeptide chains, which almost always occur in two pairs. The 4 chains of amino acids - globinssurround the iron-containing heme group which binds to O 2 . Adult humans typically have H b - A which has two alpha (α ) and 2 beta (β ) globin chains. Tha alpha and beta chains of amino acids come from different genes. There are actually 2 adjacent alpha genes on chromosome 16 in man and one beta gene on chromosome 11. We also make a small amount of alpha2/delta2 hemoglobin as adults; the delta globin gene is beside the beta globin gene. These genes are turned on in bone marrow only, which is where all of our blood cells originate. During most of the gestation period, a fetus has fetal hemoglobin or H b - F. Hb-F is a combination of alpha2/gamma2 gene products. There are two gamma genes just before the beta gene on chromosome 11; they differ by just one nucleotide so that one has the amino acid glu where the other has asp. The gamma genes are turned on starting at about 6 weeks after conception and begin to turn off before birth. During this time, the active globin genes are found in the liver. Several embryonic forms of hemoglobin (Hb-E) are made during the first 6 weeks following conception. Active genes are transcribed in the yolk sac during very early development. Along with alpha genes, there are zeta and epsilon genes expressed during this developmental period. The various forms of Hb have differing affinities for O2 ; the embryonic forms function in a relatively low O2 environment and the fetal globins must be able to take O2 from the mothers blood, as compared to adult Hb where the O 2 is absorbed in the lungs. There are a number of genetic defects where not enough hemoglobin is made. These can result from defects in the gene(s) or from defective regulation. The common name for these diseases is thalassemia. If no alpha globin is made the disease is alpha0 -thalassemia and if some but less than the normal amount is made, the disease is called alpha + -thalassemia. Beta0 and Beta+ types of thalassemia also occur. In all cases, individuals who are heterozygous for one normal gene and one defective allele may have a minor degree of anemia, but are essentially normal. Heterozygotes are often said to have thalassemia minor, while homozygous defective individuals have thalassemia major. If n o alpha globin is made, the condition is known as hydrops fetalis and is usually lethal within 24 hours after birth. When no beta globin is made, the condition is called Cooley's anemia or sometimes Mediterranean anemia reflecting the fact that it is relatively common in that area of the world. In fact, it is the cause of many thousands of childhood deaths per year around the globe. Patients have all the problems associated with severe anemia. Their system tries to get along with fetal hemoglobin but these genes naturally turn off. Very limited O2 transport can be handled by alpha4 globin, but soon the only solution is blood transfusions every 2-3 weeks. After some years of transfusions, the build-up of iron damages the liver heart and kidneys, so that patients seldom survive into their thirties. (The OMIM entry for β 0 thalassemia is: <http://www.ncbi.nlm.nih.gov:80/entrez/dispomim.cgi?id=141900> In cases where an HLA match can be found, a bone marrow transplant can effectively cure the symptoms. . Many different defects in the promoter or β -globin structural gene have been described that lead to deficiency of globin production, including deletions, new stop codons and changed intron splice signals. An interesting observation was made in patients who have a condition called "Hereditary Persistence of Fetal Hemoglobin (HPFH). These individuals get along relatively well with only fetal hemoglobin being made, even as adults. In some cases, the whole beta gene and the adjacent delta gene have been shown to be entirely missing in these individuals. This suggests that there may be some regulatory factor within or between these genes that normally functions to turn off the fetal gamma-type globins. HPFH also has spurred efforts to try to turn on the fetal Hb genes in adults with thalassemia major. One compound that can do so, at least for short a time is 5-azacytidine, a base analog that is rather toxic so can not be used without very careful monitoring. The rationale for testing 5-azacytidine came from its known ability to cause demethylation of DNA. It turns out that many of the Cs in the promoters of genes that are inactive are methylated (5-m C) but that when the same gene is active, the same Cs are not methylated. (This includes our globin genes). At this point it is still very difficult to determine whether methylation is a method for silencing genes, or a consequence of the gene already being inactive. In any case removing the methyl from 5m Cs leads to increased transcription. Again however, just as no method for selectively methylating specific promoters has been identified, 5-azaC is not specific in removing methyl groups. Thus, other genes that should remain inactive may be turned on when attempting to treat thalassemia. The treatment is used only in patients who can no longer have transfusions. In general the models for eukaryotic gene regulation are similar to the lac-operon, except that multiple trans-acting factors may attach to the same promoter; some of them stimulate transcription while other tend to decrease transcription. Thus transcription of a tissue specific or developmentally expressed gene may depend on a delicate balance of multiple interacting factors. We know that hormones are key factors in gene regulation in plants and animals. There are two types of hormones -peptides and steroids. As the name implies, peptide hormones are chains of amino acids and include molecules such as insulin, nerve growth factor, human growth hormone and many others. Peptide hormones do not enter the target cell but instead interact with receptors found on the cell surface. Once they bind, a reaction occurs on the inner side of the membrane to release another compound that is referred to as a "second messenger". In many cases the 2 nd messenger is cAMP, the same compound that signaled well-off conditions in bacteria to prevent induction of the lac operon if both glucoses and lactose are present. The second messenger can then interact with other proteins to cause a phosphate to be added or removed from another protein, setting up a cascade of steps eventually leading to active transcription factors that interact directly with DNA. Much research is underway to understand these signal transduction pathways, Steroid hormones such as estrogens and testosterone can directly enter the cell. Inside, they still tend to interact with specific receptors in order to regulate transcription. Since hormones tend to stimulate mRNA synthesis, the target sequence in the promoter that is recognized by the transcription factor (hormone & receptor or second messenger molecule) is generally referred to as an enhancer element. Many genes also have been found to have interacting "silencers" where binding of a transcription factor can prevent transcription. To be thorough, it should be noted that gene expression can also be regulated by regulating translation or even after translation by adding glucoses, phosphates, etc. to specific proteins. Many proteins such as insulin are first made as larger molecules that require specific cuts by other proteases to become active. Likewise, some proteins have a much longer "lifetime" than others, so the rate of turnover can also be important in regulating gene expression.