Sunday, November 24, 2024
11/24/2024
PROJECT SUMMARY Precise, coordinated regulation of gene expression is essential for the viability of all organisms and prevents the formation of many disease states. A critical challenge for the cell is to coordinate the regulation of thousands of genes that are distant from each other in the linear genome. Coordinate regulation of distant genes is key for diverse, essential biological processes from activation of the zygotic genome, to cellular differentiation, and dosage compensation. Our goal is to reveal how the correct genes are precisely coregulated spatially and temporally. Prior to the zygotic genome becoming activated, only a few key transcription factors (TFs), called pioneer TFs9, occupy their DNA targets. Pioneer TFs can bind closed chromatin, recruit chromatin remodelers, and target additional TFs and complexes to coregulate genes. We and others recently identified a new conserved mechanism by which GA-binding pioneer TFs coregulate genes through a new class of cis regulatory elements called tethering elements which mediate chromatin looping and are distinct from enhancers and promoters. However, it is critical to determine the mechanisms by which tethering elements function spatially and temporally to coregulate the correct targets. We leverage the conserved, dynamic process of male X- chromosome dosage compensation (DC) to define the mechanisms by which tethering elements co-regulate genes because hundreds of tethering elements co-upregulate thousands of non- contiguous active X-linked genes. Thus far, we have identified the following mechanisms that are necessary, but not sufficient to, drive the specificity of tethering elements during Drosophila DC, a powerful genetic and biochemical system: 1) long-range 3D chromatin loops mediated by a conserved pioneer TF that dimerizes and binds to clusters of GA-rich motifs; 2) competition between functionally similar GA-binding pioneer TFs; 3) pioneer TF interaction with long non- coding RNAs (lncRNAs). Based on these findings, we hypothesize that competition between similar GA-binding pioneer TFs that dimerize at clustered GA repeats and directly interact with lncRNAs drive the specific contacts that precisely co-regulate target genes spatially and temporally. We will answer the following key questions: Question #1: How does competition between pioneer TFs drive three-dimensional looping? Question #2: How does interaction between TFs and lncRNAs coregulate genes? Question #3: How is the spatial and temporal specificity of gene co-regulation determined? By defining how pioneer TFs and lncRNAs function together to accurately spatially and temporally coregulate distant genes, we will determine fundamental new mechanisms for gene regulation.
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