Abstract

Genomics approaches aim to identify all functional elements in the human genome and to understand their functions. Such large-scale approaches are thought to greatly increase insights in human biology and disease. Here it is proposed to further develop and validate a new and unique methodology to identify functional elements in the human genome. The approach is based on the hypothesis that direct physical interactions between sequence elements will point to functional relationships between them. For example, regulatory elements have been shown to physically interact with their target genes to control transcription. Similar long-range interactions between genomic elements are thought to be involved in other genomic processes such as DNA replication, repair, meiotic recombination and chromosome condensation. Therefore, identification of chromosomal interactions, and chromosome structural features in general may result in finding functional elements. This proposal entails the further development and validation of an approach that relies on determination and computational analysis of chromosomal interactions as a means to identify functional elements. Chromosomal interactions will be measured using a molecular methodology, """"""""Chromosome Conformation Capture"""""""" or """"""""3C"""""""" that we have developed. The main goal of this proposal is to assess the use of this structural approach to find functional elements.
Specific Aim 1 : Development of robust 3C-based strategies to identify functional elements in the human genome.
Specific Aim 2 : To generate two focused interaction frequency datasets for regions selected by the ENCODE project.
Specific Aim 3 : To interpret 3C interaction frequency datasets by building structural models. Analysis of the data obtained and integration of these data with results derived from other ENCODE projects is expected to provide information regarding the suitability of this chromosome structural approach to find functional elements.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
1R01HG003143-01
Application #
6750571
Study Section
Special Emphasis Panel (ZHG1-HGR-P (02))
Program Officer
Good, Peter J
Project Start
2003-09-30
Project End
2006-08-31
Budget Start
2003-09-30
Budget End
2004-08-31
Support Year
1
Fiscal Year
2003
Total Cost
$366,820
Indirect Cost

  Institution

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

  Publications

Metkar, Mihir; Ozadam, Hakan; Lajoie, Bryan R et al. (2018) Higher-Order Organization Principles of Pre-translational mRNPs. Mol Cell 72:715-726.e3
Dixon, Jesse R; Xu, Jie; Dileep, Vishnu et al. (2018) Integrative detection and analysis of structural variation in cancer genomes. Nat Genet 50:1388-1398
Kundu, Sharmistha; Ji, Fei; Sunwoo, Hongjae et al. (2018) Polycomb Repressive Complex 1 Generates Discrete Compacted Domains that Change during Differentiation. Mol Cell 71:191
Oudelaar, A Marieke; Davies, James O J; Hanssen, Lars L P et al. (2018) Single-allele chromatin interactions identify regulatory hubs in dynamic compartmentalized domains. Nat Genet 50:1744-1751
Gibcus, Johan H; Samejima, Kumiko; Goloborodko, Anton et al. (2018) A pathway for mitotic chromosome formation. Science 359:
Rodríguez-Carballo, Eddie; Lopez-Delisle, Lucille; Zhan, Ye et al. (2017) The HoxD cluster is a dynamic and resilient TAD boundary controlling the segregation of antagonistic regulatory landscapes. Genes Dev 31:2264-2281
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
Oomen, Marlies E; Dekker, Job (2017) Epigenetic characteristics of the mitotic chromosome in 1D and 3D. Crit Rev Biochem Mol Biol 52:185-204
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

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