The goals of the proposed research are to advance our understanding of the functions of the H1 linker histones and the relevance of their diversity. H1 histones are thought to facilitate the folding of chromatin into higher order structures and thereby influence gene expression and other processes requiring access to DNA. Most of the knowledge about the functions of the H1 histones has been derived from in vitro studies. This proposal will analyze the functions of H1 histones in vivo in mice. Mice and other mammals have at least 7 different subtypes of H1 histones that differ considerably in their primary sequence and expression during development. The working hypothesis to be tested in this proposal is that different H1 subtypes contribute to establishing differences in vivo chromatin structures and differences in gene regulation. The strategy for studying the function of specific H1 subtypes is to generate and characterize mice in which one or more H1 genes have been knocked out. Gene inactivation will be used to 1) determine the effect of eliminating one H1 subtype on the phenotype and on gene expression patterns in specific tissue and 2) to determine the effect of eliminating several H1 subtypes simultaneously so as to generate animals in which several tissues contain mostly one subtype or even a large deficiency in total linker histone content. The mechanisms by which H1 histones participate in regulating transcription will be analyzed by comparing the chromatin structure in the vicinity of specific genes. The proposal will also characterize a new, potentially novel H1 gene and attempt to identify other H1-related genes in the mouse genome.
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