This is a proposal to study mechanisms of gene regulation during early development using the sea urchin histone gene family as a model system. This gene family includes two subfamilies, """"""""early"""""""" and """"""""late"""""""", that are regulated differently during sea urchin development. Early histone genes are expressed maximally from fertilization to the blastula stage, late histone genes from the blastula stage onwards. This stage-specific switch in histone gene expression is the result largely of modulations of early and late gene transcription rates.
The specific aims of this proposal are (1) to locate histone DNA sequences required for the regulation of early and late histone genes during development, and (2) to identify and characterize trans-acting effector molecules that are responsible for this regulation. Histone gene regulatory sequences will be localized by a mutagenesis-gene transfer approach involving microinjection of mutant histone gene constructs into sea urchin embryos and assessing the effects of such mutations on the timing of their expression during development. The analysis of trans-acting regulators of histone gene expression will comprise three related approaches: (1) further characterization of a sea urchin nuclear factor(s), termed H2b-f1, that stimulates sea urchin early and late H2b transcript accumulation in Xenopus oocytes, (2) examination of properties of histone gene regulatory factors by competition between microinjected DNA and endogenous or coinjected histone genes for trans-acting regulatory molecules, in vivo (in the sea urchin); (3) use of """"""""genomic sequencing"""""""" for the direct examination of interactions between putative histone gene regulatory factors and histone genes in vivo. Together, these several approaches will provide a detailed picture of the control of sea urchin histone gene expression by effector molecules that interact with DNA. The proposed research is of fundamental importance to understanding molecular-genetic mechanisms underlying embryonic development. Consequently, it may prove useful in understanding of diseases, such as cancer that may result from aberrations in developmental regulatory processes.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Molecular Biology Study Section (MBY)
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University of Southern California
Schools of Medicine
Los Angeles
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