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Abstract
Understanding the control of the developmentally regulated switch of gene expression within the beta-globin locus is a main focus of research today. Clearly, globin gene transcription switches from embryonic to fetal to adult forms in humans and embryonic to adult in chickens during development. The expression of the genes on the beta-globin locus is controlled by a series of both general and tissue-restricted transcription factors. In addition, recent models of globin switching have focused on competition and cooperation between enhancers, promoters, and the locus control region (Bulger and Groudine, 1999). In this paper we will analyze both the human and chicken £]-globin locus. From this, we identify the similarities and differences of the locus among the two species and present different methods involved in activation.
Introduction
The £]-Globin Gene is one of two genes that make up a multigene family. Members of a multigene family not only share DNA-sequence homology, but also have gene products that are functionally associated (Klug and Cummings, 566). The globin genes of vertebrates¡¦ expression are both developmentally and temporally regulated (Choi and Engel, 1986; Dolan et. ... The two regions that make up the globin gene family include the alpha-globin and beta-globin genes (Ioudinkova et. ...
Hemoglobin synthesis requires the synchronized production of both heme and globin. While heme is the prosthetic group that can reversibly bind to oxygen, globin is the protein that encloses and safeguards the heme molecule.
The £- and £]-globin loci, in all vertebrate species, are assembled with multiple genes encoding distinct globin protein isotypes (Foley and Engel, 1992). The expression of these proteins is regulated, primarily at the transcriptional level, during both erythroid cellular differentiation and embryonic development (Foley and Engel, 1992).
Mammalian £]-globin locus
The beta-globin locus in most mammals consists of five functional beta-globin genes that are located on the short arm of chromosome 11 (Baron, 1997; Harju et. ... The order of the genes is: epsilon, gamma, delta, and beta (Gribnau et. ... On the beta region, the genes are arranged consecutively from 5¡¦ to 3¡¦ beginning with the gene that is usually expressed first known as the £`-globin gene. This particular gene is generally expressed during embryonic development. Following this gene are the two nearly identical gamma genes, G£^ and A£^ that are expressed during fetal development. ... After birth, the £_-globin and £]-globin genes are expressed. It is during this time that the formation of £^-globin depreciates with an increase in £]-globin synthesis. ... The £_-gene, which is positioned between the £^- and £]-genes, produces only a small amount of £_-globin in the fetus and adults (Ristaldi et. ... The product of the £_-globin gene, hemoglobin A2, is made up of two £-chains and two £_-chains. ... The last functional gene on the beta globin locus is the £]-globin gene. This gene is responsible for the major hemoglobin in adults, hemoglobin A. This specific hemoglobin is a tetrameric protein that includes two identical £-globin chains and two £]-globin chains (Klug and Cummings, 567).
The hemoglobin proteins that are encoded from the epsilon and gamma genes have a higher binding affinity for oxygen than the adult hemoglobin¡¦s that result from the delta and beta genes. ...
The £]-globin locus also contains a single pseudogene, £r£]1, within the group. A pseudogene is a nonfunctional gene with sequence homology to a known structural gene present elsewhere in the genome (Klug/Cummings, 766). ...
Regulatory sequences that include both positive and negative elements in the promoter region are located 5¡¦ and 3¡¦ to the £]-globin gene (Engel and Tanimoto, 2000). There are also additional positive elements within and downstream of the gene. One particular regulatory element is made up of four strong erythroid-specific DNase I hypersensitive sites (HS1, HS2, HS3, and HS4) extending from 6-18kb upstream of the 5¡¦ epsilon-globin gene (Baron, 1997; Gerasimova and Corces, 2001). This element, the locus control region (LCR), promotes full levels of expression of the five genes on the beta-globin locus. ... It possesses very strong enhancer activity and functions in the development of an open (active) chromatin structure extending over the entire locus (Baron, 1997). LCRs are functionally defined by their ability, in transgenic assays, to direct high-level, tissue-specific expression of linked genes at all sites of integration examined and at moderately constant levels per gene copy (Bulger and Groudine, 1999).
Approximate Word count = 3537
Approximate Pages = 14.1
(250 words per page double spaced)
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