The findings may point researchers to future gene therapies for patients with sickle cell anemia and beta-thalassemia.
Inthe October issue of Blood, the journal of the American Association forHematology, researchers demonstrated that a protein called KLF2regulates the production of embryonic globin genes and the maturationand stability of embryonic red blood cells in a mouse model.Researchers observed that KLF2 is responsible for controlling and“turning on” the embryonic globin gene.
“Understanding how genesare turned on and off, and the switch from the embryonic globin gene tothe adult beta-globin gene has clinical relevance to treatment ofsickle cell anemia and beta-thalassemia,” said Joyce A. Lloyd, Ph.D.,associate professor of Human Genetics at VCU, and corresponding authorfor this study.
“Our findings are significant for futuretreatment of these blood disorders, potentially using gene therapiesand other novel strategies,” she said. In gene therapy, a normal DNA isinserted into cells to correct a genetic defect. To correct the defector mutation, a gene may be replaced, altered or supplemented.
Accordingto Lloyd, the production of blood cells involves a complexdifferentiation pathway that involves the interaction of many molecularplayers and proteins.
In humans, there are four globin genesclustered on chromosome 11 in the order in which they are “turned on”or expressed. These genes include the epsilon-globin gene, twogamma-globin genes and the beta-globin gene. Lloyd said that duringfetal development, the embryonic epsilon-globin gene is active first,followed by the gamma-globin genes, and finally the adult form,beta-globin takes control following birth.
Lloyd and PriyadarshiBasu, Ph.D., lead investigator at VCU, and the research team comparedmice that were missing the gene for KLF2 to normal mice. They foundthat the KLF2-deficient mice produced embryonic red blood cells thatappeared abnormal, were more likely to undergo cell death, and producedsignificantly lower amounts of globin mRNA than those found in normalmice. Globin mRNA is a key player in gene expression that helpstranslate the DNA’s genetic code.
Lloyd and her colleaguesidentified that the role of KLF2 for the embryonic epsilon-globin genesis analogous to that of a protein called EKLF. EKLF plays a centralrole in the developmental regulation of the adult beta-globin gene, andis essential for the maturation and stability of adult red blood cells.Researchers believe that the roles of EKLF and KLF2 may partiallyoverlap in controlling human embryonic and fetal globin gene expression.
This research was supported by a grant from the National Institutes of Health.
Lloydcollaborated with colleagues in the VCU Department of Human Genetics,and the VCU Department of Anatomy and Neurobiology; the Department ofMolecular Genetics, Biochemistry and Microbiology at the University ofCincinnati; and the Department of Medicine at the University ofCalifornia-San Francisco.
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