The 3D structural organization of the genome plays a key role in nuclear functions such as gene expression and DNA replication. One of the next grand challenges of biology is to determine the detailed 3D genome architecture and elucidate its functional implications. In this proposal, we aim to develop a suite of novel technologies for comprehensive structural and dynamic analyses of genomes, in two aspects: (1) the spatial interactions and higher-order organization of genomic DNA and (2) the functional organization of protein complexes driving the 3D folding of genomes. The new computational and experimental methods proposed herein integrate multiple experimental inputs and generate physical higher-order models of the 3D nuclear genome organization. Analysis of these models will yield new insights into the principles and structure/functions relationships of the genome's 3D organization in space and time. We have the following aims: (1) Develop technologies for mapping the relative spatial positions of genomic DNA in the nucleus: our focus will be on the three major technical barriers faced by all current mapping technologies, namely inefficient and potentially biased data acquisition, lack of temporal resolution, and missing higher-order contact information. (2) Develop technologies for deciphering the Protein Code of 3D genome organizations: we will employ a proven pipeline for the isolation of native protein complexes, but extensively optimized for the purpose of reading out the chromatin interactome surrounding each particular chromatin interacting region. (3) Develop technologies for modeling and analysis of 3D genome structures: we will develop an integrated platform for population-based modeling of 3D genome structures, and develop a series of computational tools to perform structure-function mapping on the 3D genomes. (4) Develop sold validation techniques for guiding the above technology innovations: we will develop a set of simple-to-implement and easy-to-interpret techniques to validate our novel technologies, and this techniques can be generally adopted by the community for similar validation purposes.

Public Health Relevance

The 3D architecture of genomes are critical for the execution of a variety of cellular functions, and defects in spatial genome organizations are relevant for physiological and pathological processes. Technologies developed in this project will significantly facilitate our understanding of 3D genome structures, and provide possible missing links between genomes and diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZRG1)
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Blondel, Olivier
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University of Southern California
Schools of Arts and Sciences
Los Angeles
United States
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Kim, Seung Joong; Fernandez-Martinez, Javier; Nudelman, Ilona et al. (2018) Integrative structure and functional anatomy of a nuclear pore complex. Nature 555:475-482
Caridi, Christopher P; Delabaere, Laetitia; Tjong, Harianto et al. (2018) Quantitative Methods to Investigate the 4D Dynamics of Heterochromatic Repair Sites in Drosophila Cells. Methods Enzymol 601:359-389
Hua, Nan; Tjong, Harianto; Shin, Hanjun et al. (2018) Producing genome structure populations with the dynamic and automated PGS software. Nat Protoc 13:915-926
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Li, Qingjiao; Tjong, Harianto; Li, Xiao et al. (2017) The three-dimensional genome organization of Drosophila melanogaster through data integration. Genome Biol 18:145
Dai, Chao; Li, Wenyuan; Tjong, Harianto et al. (2016) Mining 3D genome structure populations identifies major factors governing the stability of regulatory communities. Nat Commun 7:11549
Tjong, Harianto; Li, Wenyuan; Kalhor, Reza et al. (2016) Population-based 3D genome structure analysis reveals driving forces in spatial genome organization. Proc Natl Acad Sci U S A 113:E1663-72
Shin, Hanjun; Shi, Yi; Dai, Chao et al. (2016) TopDom: an efficient and deterministic method for identifying topological domains in genomes. Nucleic Acids Res 44:e70

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