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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
2R01HG003143-10
Application #
8761622
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Pazin, Michael J
Project Start
2003-09-30
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Belaghzal, Houda; Dekker, Job; Gibcus, Johan H (2017) Hi-C 2.0: An optimized Hi-C procedure for high-resolution genome-wide mapping of chromosome conformation. Methods 123:56-65
Nora, Elphège P; Goloborodko, Anton; Valton, Anne-Laure et al. (2017) Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization. Cell 169:930-944.e22
Schalbetter, Stephanie Andrea; Goloborodko, Anton; Fudenberg, Geoffrey et al. (2017) SMC complexes differentially compact mitotic chromosomes according to genomic context. Nat Cell Biol 19:1071-1080
Kundu, Sharmistha; Ji, Fei; Sunwoo, Hongjae et al. (2017) Polycomb Repressive Complex 1 Generates Discrete Compacted Domains that Change during Differentiation. Mol Cell 65:432-446.e5
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Giorgetti, Luca; Lajoie, Bryan R; Carter, Ava C et al. (2016) Structural organization of the inactive X chromosome in the mouse. Nature 535:575-9
Smith, Emily M; Lajoie, Bryan R; Jain, Gaurav et al. (2016) Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus. Am J Hum Genet 98:185-201
Barutcu, A Rasim; Lajoie, Bryan R; Fritz, Andrew J et al. (2016) SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells. Genome Res 26:1188-201

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