The Investigator plans to continue his work examining the mechansim of globin gene switching using a transgenic mouse model. Dr. Townes holds that developmental switching in globin gene expression is due to competition for LCR enhancer activity by various transacting factors that associate with the globin gene promoters during different stages of maturation. The HS2 region of the LCR appears to be particularly important in this regard. He advances the hypothesis that sequential activation of the globin genes is due to the serial movement of the LCR into apposition with promoters of the various globin genes, producing transcriptionally active complexes. The transcriptional complexes produce a series of enlarging DNA loops as the LCR is brought into physical contact with globin gene promoters that are progressively further downstream. The -202 to -54 region of the gamma-globin promoter may be important in the proper expression of the gamma and beta-globin genes. The investigator has recently described a new erythroid-specific transcription factor, LCR-F1, that modulates globin gene expression.
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