REGULATION OF HISTONE GENE EXPRESSION IN MAMMALS

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Histones are the major proteins in chromatin and act to package the DNA into nucleosomal structures. The recent characterization of a wide variety of variant and modified histones which are temporally and spatially regulated has implicated these proteins in control of gene expression during differentiation and aging. The ultimate purpose of this proposal is to determine the molecular mechanisms by which histone genes are so diversely regulated in order to approach questions regarding the function of these proteins. This will be accomplish by the detailed analysis the transcriptional, translational, and temporal regulation two members of the H3 subtype of histones. Particular attention will be paid to the detailed molecular structure of these genes and their mRNAs in an effort to determine what mechanisms control their expression. Initially, a descriptive analysis will be performed in order to carefully characterize the regulation of these genes. Subsequently, hybrid gene constructions and deletion mutations will be used to determine sequence elements that control cell cycle and variant gene expression at both the transcriptional and translational levels. Additionally, the function of the introns within H3 genes will be analysed to determine the consequences to cell cycle control and to nuclear processing and transport of the addition of introns to the H3.1 gene and the deletion of introns from the H3.3 gene. In addition, the functional significance of the highly conserved intronic region, and the potential functional role of the transcription termination site within the first intron will be analysed.