Grant: Operating Grant

In order to fit inside the small volume of a nucleus, mammalian genomes must be tightly packaged in vivo. Genome folding and organization is important not only to reduce the length of chromosomes but also because it represents a novel type of gene regulation mechanism. For example, it was found that gene expression could be controlled by the formation of DNA loops. Interestingly, these DNA loops were found only in cells expressing the target genes, indicating that genome organization is tissue-specific and important for proper gene expression. This notion is reinforced by the discovery of single nucleotide polymorphisms (SNPs) in cancers that create novel enhancers acting long-range to activate distal genes through DNA looping. Thus, how a genome is organized is functionally relevant not only because it can reflect its transcriptional state, but also since the way it folds can determine which long-range contacts are possible by promoting or restricting physical proximity between chromatin segments. For this reason, defining how genomes are organized is essential to understand how correct expression is obtained. To address this question, we suggest mapping genome organization during cellular differentiation to identify genome architectures that contribute to cell type specificity. Our hypothesis is that cellular differentiation occurs with changes in the three-dimensional organization of chromosomes, and that these changes determine whether genes can be regulated long distance by control elements.