Molecular Genetics of the Red Cell Membrane Skeleton

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DESCRIPTION (provided by applicant): This proposal has as its long-term objective the elucidation of molecular mechanisms involved in the expression of genes encoding proteins of the membrane skeleton, in particular the genes encoding the spectrins, important constituents of the membrane skeleton of erythrocytes as well as nonerythroid cells. Study of these genes is of scientific interest because of the diversity of isoforms that these genes produce in erythroid and nonerythroid cells. This diversity presents the opportunity to investigate at the molecular level mechanisms involved in tissue-specific gene expression in specialized tissues, including associated changes in chromatin structure, use and regulation of alternative promoters and regulation of tissue-specific alternative splicing. A detailed analysis of these mechanisms using members of a gene family that are structurally very similar, but behave very differently in their pattern of expression in various tissues, can provide important insights in the molecular biology of gene expression in eukaryotes. In addition, there is biological and medical interest in the spectrins because mutations in the erythroid gene are associated with hereditary hemolytic anemias, and because the non-erythroid gene products have been implicated in some important neurological functions. The proposed experiments include: identification and characterization of cis determinants that regulate the tissue specific transcription of the erythroid beta-spectrin gene; study of the chromatin structure in which the beta-spectrin gene is embedded in erythroid and muscle cells that express the gene; and study of the molecular mechanisms involved in the post-transcriptional pre-mRNA processing events, such as alternative cleavage-polyadenylation and alternative splicing, that result in the production of different C-terminal isoforms of beta-spectrin in different tissues.