Transcriptional regulation is a key mechanism that controls many fundamental biological processes such as cell growth and differentiation. A main interest of my lab is to understand the biology and mechanism of action of Yin Yang 1(YY1), a zinc finger-containing transcription factor that can both repress and activate transcription. The functional significance of YY1 is highlighted by the fact that adenovirus E1A regulates YY1 transcriptional activity, and this regulation appears to be important for E1A to induce oncogenic transformation and to inhibit differentiation. Consistent with this, cell culture studies suggest that YY1 may play a role in cell growth and differentiation. Recently, a Drosphila YY1 homolog has been identified as a member of the Polycomb group (PcG) proteins that are involved in stable repression of target genes in development. Some PcG members also appear to be involved in oncogenesis. Therefore, insights into YY1 function and mechanism of action in vivo are likely to enhance our understanding of cell growth control and tumorigenesis. A major goal of this proposal is to seek insights into the biology of YY1 in a living organism (mouse), an in so doing generate critical tools with which to study YY1 transcriptional mechanisms in a physiologically relevant context. Using a homologous recombination-based knock-out approach, we have recently identified an essential role for YY1 during early mouse embryogenesis. In this application, we propose to study YY1 function in specific development/differentiation pathways by generating and analyzing mice carrying conditional alleles of YY1. As a complementary approach, we will isolate a variety of YY1 deficient cells in which to conduct in-depth biochemical and molecular studies of YY1 in cell growth and differentiation. With these cells, we will also identify in vivo YY1 target genes and investigate molecular mechanisms by which YY1 activates and represses genes in their natural chromosomal locations. Finally, we will investigate the biological significance and mechanism of action of a newly identified, evolutionarily conserved YY1 repression domain. Taken together, the proposed experiments will provide significant novel insights into the function and mechanism of action of YY1 in vivo. The findings from these studies will also have broad implications for understanding how transcription factors regulate cell growth and differentiation in a living organism, and transcriptional regulatory mechanisms in mammals in general.
