Transcription cofactors in differentiation

Harvard Medical School, Boston MA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): In C. elegans early embryos, the initial cell fate specification is controlled by a transcription network consisting of maternally provided transcriptional regulators. The intent of this investigation is to decipher the molecular events controlled by the histone acetylase CBP-1 and the deacetylase HDA-1. Mammalian homologs of these proteins have been implicated in differentiation and tumorigenesis, highlighting their importance in cell growth and differentiation. We previously showed that CBP-1 and HDA-1 play opposing roles in C. elegans early embryogenesis. Our recent data suggest that CBP-1 and HDA-1 may exert their antagonistic effects by regulating overlapping sets of target genes. Initial global gene profiling to test this model identified a surprising preference of HDA-1 for tissue-specific genes, suggesting that new paradigms may emerge from this genome-wide approach. In addition to histone modification, we identified a Wnt nuclear effector as a new target that is directly regulated by CBP-1. Lastly, though ubiquitously expressed, HDA-1 and related HDA-2 and 3 also play a specific role in embryonic posterior development, highlighting the complexity of their biological roles. These exciting findings form the basis of this proposal. In this application, we will use both genetic, molecular and genome-wide approaches to delineate mechanisms underlying the biological functions of CBP-1 and HDA-1 in C. elegans. We will use microarray technology to elucidate molecular events controlled by CBP-1 and HDA-1 at specific stages during early embryogenesis. These experiments will test the model that CBP-1 and HDA-1 converge their action on overlapping, and possibly tissue-specific genes. Significantly, findings will enable us to begin to describe, in molecular terms, the cascade of events important for early embryonic development that involve histone acetylation and deacetylation. We will also investigate how CBP-1 and perhaps additional acetylases directly regulate POP-1, a Wnt nuclear effector, through acetylation, and to determine if and how acetylation and Wnt signaling functionally interact to control POP-1 localization in the developing worm embryos. Finally, we will identify molecular mechanisms underlying the requirement of HDA-1, 2 and 3 in embryonic posterior development. Taken together, the proposed studies will provide significant novel insight into the biology and mechanism of action of CBP-1 and HDA-1 in a living organism, C. elegans, and will shed significant new light on how their homologous proteins function in mammals. [unreadable] [unreadable]