Coregulation of genes by pioneer transcription factors and noncoding RNAs - Project Summary Spatial and temporal co-regulation of genes is essential for development and prevents the formation of disease states from cancer to neurodegeneration. Despite decades of research, the mechanisms by which any specific group of target genes is co-regulated at the right time and place remain unknown. To mechanistically understand how co-regulation of genes is achieved, my research program defines new combinatorial rules for precise spatial and temporal coregulation. Revealing the rules that drive coregulation of specific subsets of genes is highly significant because it advances our understanding of gene expression across space and time which has the potential to ultimately enable the correction of misregulated gene expression in disease contexts. To reveal the rules that govern the co-regulation of specific subsets of genes, it is essential to understand how different classes of regulatory factors function together to co-regulate the correct target genes spatially and temporally. Two key classes of factors that we and others have determined co-regulate the same groups of genes across species are: 1) DNA-binding transcription factors (TFs) and 2) long non-coding RNAs (lncRNAs). However, very little is known about how TFs and lncRNAs function together to regulate specific groups of target genes. Recently, we and others discovered that competition versus synergy between GA-binding pioneer TFs can co-regulate distant genes by increasing the 3D proximity of tethering elements, a new conserved class of gene regulatory element. LncRNAs also associate with tethering elements to co-regulate subsets of genes by poorly understood mechanisms that may involve regulating 3D genomic contacts. Therefore, the function of tethering elements is regulated by associating with both pioneer TFs and lncRNAs, but how these regulatory factors function together to specifically target the correct group of genes for co-regulation is not understood. We will answer the following key questions: Question #1: How does competition between pioneer TFs with similar binding sites coregulate specific groups of genes in 3D? Question #2: How do interactions between pioneer TFs and lncRNAs coregulate specific groups of genes? Question #3: How do pioneer TFs and lncRNAs coregulate specific groups of genes over time and space? Our overall hypothesis is: Competition between GA-binding TFs and specific interactions between TFs and lncRNAs combine to three-dimensionally link the correct regions of the genome for co-regulation of gene expression over time and space. My research program will test this hypothesis by combining diverse methods including genetics, genomics, biochemistry, single particle imaging, and new computational approaches to define the combinatorial rules by which genes are co-regulated across space and time.
