The three-dimensional organization of the genome plays a critical role in the regulation of gene expression, but the mechanisms by which it is established and maintained are not well understood. Drosophila represents an ideal model system to study these processes. Architectural proteins, also known as insulator proteins, were first found in Drosophila. Contrary to other model organisms such as S. cerevisiae, C. elegans, or A. taliana, Drosophila shows the same organization into Topologically Associating Domains (TADs) and compartments found in mammalian cells. In vertebrates, CTCF and cohesin are the main architectural proteins studied in detail, although other proteins found to interact or co-localize with CTCF could also play a role in genome 3D organization. In addition to CTCF and cohesin, Drosophila has a large number of architectural proteins that bind DNA directly or are recruited to chromatin indirectly. Work we have carried out during the current funding period has resulted in the understanding of how these proteins are organized in the genome and their roles in 3D organization. Individual DNA- binding architectural proteins recognize DNA motifs at specific sites and recruit a variety of accessory proteins to form architectural protein binding sites (APBSs). The number of DNA- binding and accessory proteins, i.e. the degree of occupancy at specific sites in the genome, determines their role in 3D organization, with highly occupied APBSs present at boundaries between TADs. High gene density and transcription are also enriched at boundaries between TADs, and inhibition of transcription results in alterations in 3D organization. In this application we propose experiments to dissect the mechanism responsible for chromosome 3D organization and determine the relative contribution of architectural proteins and transcription to this process. We will establish correlations between architectural protein localization, transcription, and 3D organization by examining these three features during the heat shock response, in sperm, during early embryonic development, and in mitotic chromosomes. In addition, we will determine the causal effect of architectural proteins and transcription by examining their effect on 3D organization using transgenes, containing APBSs or expressed reporter genes, in a specific region of the genome. Results from this work will inform a computer simulation algorithm able to predict 3D organization from the properties of APBSs and transcriptional state. The ultimate goal of this work is to establish general rules that take into account the contribution of these two factors to explain how chromosomes fold in all organisms from yeast to mammals.
This study will analyze the mechanisms by which the three-dimensional organization of the genetic material in the nucleus is established and maintained. This organization is critical for the regulation of gene expression, and the results will be important to understand how stem cells differentiate and somatic cells are reprogrammed. This knowledge will be essential when using stem cell therapy to treat human diseases.
| Rowley, M Jordan; Corces, Victor G (2018) Organizational principles of 3D genome architecture. Nat Rev Genet 19:789-800 |
| Nichols, Michael H; Corces, Victor G (2018) A tethered-inchworm model of SMC DNA translocation. Nat Struct Mol Biol 25:906-910 |
| Xu, Chenhuan; Corces, Victor G (2018) Genome-Wide Mapping of Protein-DNA Interactions on Nascent Chromatin. Methods Mol Biol 1766:231-238 |
| Lyu, Xiaowen; Rowley, M Jordan; Corces, Victor G (2018) Architectural Proteins and Pluripotency Factors Cooperate to Orchestrate the Transcriptional Response of hESCs to Temperature Stress. Mol Cell 71:940-955.e7 |
| Ando-Kuri, Masami; Rivera, I Sarahi M; Rowley, M Jordan et al. (2018) Analysis of Chromatin Interactions Mediated by Specific Architectural Proteins in Drosophila Cells. Methods Mol Biol 1766:239-256 |
| Arzate-Mejía, Rodrigo G; Recillas-Targa, Félix; Corces, Victor G (2018) Developing in 3D: the role of CTCF in cell differentiation. Development 145: |
| Rowley, M Jordan; Nichols, Michael H; Lyu, Xiaowen et al. (2017) Evolutionarily Conserved Principles Predict 3D Chromatin Organization. Mol Cell 67:837-852.e7 |
| Hashimoto, Hideharu; Wang, Dongxue; Horton, John R et al. (2017) Structural Basis for the Versatile and Methylation-Dependent Binding of CTCF to DNA. Mol Cell 66:711-720.e3 |
| Jung, Yoon Hee; Sauria, Michael E G; Lyu, Xiaowen et al. (2017) Chromatin States in Mouse Sperm Correlate with Embryonic and Adult Regulatory Landscapes. Cell Rep 18:1366-1382 |
| Gómez-Díaz, Elena; Yerbanga, Rakiswendé S; Lefèvre, Thierry et al. (2017) Epigenetic regulation of Plasmodium falciparum clonally variant gene expression during development in Anopheles gambiae. Sci Rep 7:40655 |
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