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The beta-globin locus
Other Talks in the Series: Epigenetics, Chromatin, Transcription and Cancer
The basal transcription machinery for RNA polymerase II
- Prof. H. T. Marc Timmers
- University of Utrecht, The Netherlands
The Myc transcription factor network
- Prof. Robert N. Eisenman
- Fred Hutchinson Cancer Research Center, USA
This is Ann Dean I'm an investigator at the National Institutes of Health in the National Institute of Diabetes and Digestive and Kidney Diseases. The hemoglobin genes are the subject of my research, in particular, the regulation of these genes at the level of chromatin and at the level of nuclear folding of chromosomes.
The beta globin locus has long served as a major paradigm for studies of eukaryotic gene regulation and transcription. In mammals, the alpha and beta globin loci encode the polypeptides that form the heteromeric hemoglobin protein molecule. Hemoglobin is a 64-kilodalton protein consisting of four polypeptide chains. Two so-called beta-like globin chains and two alpha-like globin chains. In each tetramer, the four globin chains are held together by noncovalent attractions. The human hemoglobin tetramer is depicted in the drawing. The alpha2 beta2 tetramer is called hemoglobin A, or HbA, and is the predominant hemoglobin in adults. Each chain contains a heme group, labeled in the picture, which coordinates an iron atom. This moiety gives hemoglobin its characteristic red color. Hemoglobin transports oxygen and CO2 in the bloodstream.
This scanning electron micrograph illustrates the classic disc shape of erythrocytes, or red blood cells. In adults, during the later stages of erythroid differentiation, the genes in both the alpha and beta globin loci are expressed at exceptionally high rates. This is necessary to fill the terminally differentiated erythrocyte with hemoglobin. Naturally-occurring mutations show that coordinated regulation of the two loci is required, since imbalance between the alpha and beta globin chains leads to anemia. How the alpha and beta globin genes achieve this balanced protein production is not known. The iron atom at the center of each heme group reversibly binds oxygen in the alveoli of the lungs, and releases it in peripheral tissues in small capillaries. The oxygen is then used for the metabolic needs of cells. In these tissues, CO2 is loaded for the return trip to the lungs through the venous system, where it is exchanged again for oxygen.