Genomes perform several critical tasks to ensure normal development, homeostasis and health. First, gene transcription needs to be accurately regulated and defects in gene regulation can result in human diseases such as cancer and diabetes. Second, chromosomes need to be replicated and then accurately and reliably transmitted to daughter cells. Chromosome segregation requires extensive chromosome compaction. Defects in this process can lead to genome instability, aneuploidy and cancer. Recent studies have revealed that the spatial organization of chromosomes is a major factor in controlling both gene expression and chromosome segregation. The work proposed here will for the first time characterize the three-dimensional (3D) arrangement of chromosomes during different stages of the cell cycle at unprecedented resolution which will allow the identification of cis-elements involved in the 3D folding of chromosomes. A set of novel and powerful genomic technologies (5C and Hi-C) that allow the mapping of 3D chromosome folding will be applied to the study of the human genome. These technologies will be combined with the use of synchronous cell populations and genome-wide analysis of regulatory elements to characterize the different chromosome conformations during the cell cycle and to identify the cis-elements and some trans-factors involved. In addition, the processes that determine 3D folding of the genome, such as transcription and modulation of DNA topology will be studied. This project will provide answers to long-standing questions related to long-range gene regulation, chromosome segregation, the epigenetic transmission of transcription profiles to daughter cells, and the still largely mysterious process of formation of compact metaphase chromosomes.

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 determine the 3D folding of chromosomes and how that folding is related to the appropriate regulation of the human genome.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
5R01HG003143-09
Application #
8468942
Study Section
Special Emphasis Panel (ZRG1-GGG-F (02))
Program Officer
Pazin, Michael J
Project Start
2003-09-30
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$734,468
Indirect Cost
$287,983
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Mizuguchi, Takeshi; Fudenberg, Geoffrey; Mehta, Sameet et al. (2014) Cohesin-dependent globules and heterochromatin shape 3D genome architecture in S. pombe. Nature 516:432-5
Giorgetti, Luca; Galupa, Rafael; Nora, Elphège P et al. (2014) Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription. Cell 157:950-63
Kellis, Manolis; Wold, Barbara; Snyder, Michael P et al. (2014) Defining functional DNA elements in the human genome. Proc Natl Acad Sci U S A 111:6131-8
Nora, Elphege P; Dekker, Job; Heard, Edith (2013) Segmental folding of chromosomes: a basis for structural and regulatory chromosomal neighborhoods? Bioessays 35:818-28
McCord, Rachel Patton; Nazario-Toole, Ashley; Zhang, Haoyue et al. (2013) Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome. Genome Res 23:260-9
Naumova, Natalia; Imakaev, Maxim; Fudenberg, Geoffrey et al. (2013) Organization of the mitotic chromosome. Science 342:948-53
Kumar, Satyendra; Wuerffel, Robert; Achour, Ikbel et al. (2013) Flexible ordering of antibody class switch and V(D)J joining during B-cell ontogeny. Genes Dev 27:2439-44
Dekker, Job; Marti-Renom, Marc A; Mirny, Leonid A (2013) Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat Rev Genet 14:390-403
Phillips-Cremins, Jennifer E; Sauria, Michael E G; Sanyal, Amartya et al. (2013) Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell 153:1281-95
Kaplan, Noam; Dekker, Job (2013) High-throughput genome scaffolding from in vivo DNA interaction frequency. Nat Biotechnol 31:1143-7

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