The spatial organization of chromosomes plays important roles in regulation of gene expression and maintenance of genome stability. Detailed knowledge of the spatial arrangements of chromosomes will help elucidate the molecular mechanisms that regulate the human genome, and will provide insights into the genetic basis of human disease. We have developed powerful molecular and genomic technologies to probe the three-dimensional structure of chromosomes. These methods allow the analysis of chromosome folding through the comprehensive analysis of long-range chromosomal interactions between widely separated functional elements, such as promoters and enhancers. We have applied these technologies to human cells during cell division and discovered that chromosomes can be organized in two fundamentally distinct three- dimensional structures: one structure, observed in interphase cells, is composed of a hierarchy of different types of chromosomal domains and chromatin loops. This structure is dedicated to gene regulation. A second structure is observed in mitotic cells, when chromosomes become condensed in preparation of cell division. We discovered that this structure is best described as a linearly organized longitudinally compressed array of consecutive chromatin loops. Here we propose to first study these two distinct chromosome conformations in more detail, and then to study the genomic elements and mechanisms cells employ to build each structure. Our proposed studies will lead to insights into the finer-scale organization of chromosomes and the intricate folding pathways that connect interphase and mitotic chromosome structures.
The human genome contains all genetic information required for normal human development. The three- dimensional (3D) organization of the genome inside living cells is emerging as a critical determinant of controlling the genome, and defects in 3D genome organization can lead to human diseases such as cancer and diabetes. This proposal aims to unravel the mechanisms by which cells modulate the 3D folding of their genome to regulate gene expression and to faithfully transmit chromosomes to daughter cells.
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