The main function of red blood cells, which carry and exchange oxygen, depends on hemoglobin, a heterotetramer composed of two a and two ?-globin chains and associated iron-binding heme groups. Mutations of globin genes are among the most common inherited diseases and cause mild or severe anemia in the human population. Current treatments of severe anemia are largely unsatisfactory and it is anticipated that knowledge of how the globin genes are regulated will aide in the development of novel therapies. Erythroid-specific expression of the globin genes requires cis-regulatory DNA elements located in gene proximal or distal regions. The ?-like globin genes are regulated by a locus control region (LCR), which is composed of several DNase I hypersensitive (HS) sites and located far upstream of the genes. HS2 is perhaps the most powerful regulatory element in the LCR. It consists of several binding sites for hematopoietic and ubiquitously expressed transcription factors. One of these sites is an E-box that interacts with the helix-loop-helix protein USF. USF also interacts with E-box elements in the ?-globin gene promoter and previous work has shown that USF is required for efficient recruitment of RNA polymerase II (Pol II) to LCR element HS2 and to the ?-globin gene promoter. In addition, we have shown that USF mediates the boundary activity of the chicken 2-globin insulator HS4, which maintains an accessible chromatin conformation over the globin genes in erythroid cells. Our preliminary data demonstrate that USF1 interacts with large co-activator complexes containing two histone methyltransferases PRMT1 and hSET1. We hypothesize that USF recruits histone modifying enzymes to establish and/or maintain an open chromatin structure at boundary elements and at regulatory elements in the ?-globin locus, which in turn controls erythroid-specific and developmental stage-specific globin expression. We will test the function of USF and associated histone modifying enzymes in establishing and maintaining chromatin barrier function and tissue specific transcriptional regulation of the ?-globin locus. Finally, we will investigate how the stability of USF is regulated during differentiation of erythroid cells. Our studies on epigenetic alterations in the ?-globin gene locus are anticipated to provide new insight into the transcriptional control of globin genes and may lead to novel strategies for the molecular therapy of anemia. Furthermore, addressing the role of USF in ?-globin gene regulation may shed light on the mechanisms involved in enhancer promoter interactions.
Project Narrative: ?-globin, an important component of hemoglobin, plays a critical function in the transport and exchange of oxygen in red blood cells in which genetic defects of this gene have been implicated in mild to severe anemia. In this proposal, we will investigate the epigenetic mechanisms by which nuclear proteins USF1/2 regulate globin gene expression and chromatin barrier function in the globin loci. The studies will provide a novel insight into USF function in the regulation of developmental stage-specific globin gene expression and will lead to novel strategies for the molecular therapy of anemia.
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