SPP 2202:  Spatial Genome Architecture in Development and Disease

• Subject Area: Biology ; Medicine
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 402733153

Eukaryotic genomes encode the information that defines both general and specific characteristics of each cell type. However, the linear DNA sequence alone often fails to predict cellular functions and phenotypic outcomes. In fact, genomic information is modified and regulated by a number of additional layers of gene expression control. One of these, the spatial folding of chromosomes, has been recently identified as a critical such layer. Spatial chromosomal folding is established through binding of transcription factors as well as via epigenetic mechanisms and biophysical forces that act in a concerted manner to regulate gene expression in space and time. Therefore, studying the principles of three-dimensional chromatin folding allow us to unravel its contribution in gene regulation during development and disease. The primary goal of this Priority Program is to dissect the structure-to-function relationship of the genomes of higher metazoans at high spatiotemporal resolution in study systems relevant to genome integrity, development, and disease. Aside from the apparent goal of bringing together a critical mass of German-academia groups engaged in this line of research, we also aspire to host projects in this SPP that undertake in vitro and in vivo functional and mechanistic studies on model organisms and human samples that can deepen our understanding of how genome architecture underlies cell and tissue physiology. All projects (collaborative or standalone) should have a clear and substantial focus on mechanisms and forces driving or maintaining 3D chromatin folding and its role in gene regulation. A combination of advanced molecular methods, super‐resolution and/ or live‐cell imaging, precision genetic editing, and novel computational tools is envisaged. Thus, projects included in this 2nd SPP funding period should: (i) develop and apply novel technologies that can capture spatial chromatin conformation, also in conjunction with other genomic features (e.g., transcription, histone modifications, DNA methylation), to resolve and track features of genomic architecture in the nucleus down to the single cell-level; (ii) dissect the functional impact of 3D chromatin folding on gene expression or genome integrity in vitro and in vivo during development or cell differentiation; (iii) causally connect 3D chromatin folding with disease etiology via precision genome editing and patient data and/or disease models; (iv) develop and apply novel computational approaches allowing us to integrate, quantitatively model, and visualize the end-effects and dynamics of spatial genome organization. In the end, we aspire that the consortium will generate new knowledge bringing us closer to defining a parsimonious set of rules that explain the structure-to-function relationship of eukaryotic chromosomes.

• DFG Programme: Priority Programmes

Projects

• 3D chromatin organisation in direct neuronal reprogramming – re-shaping the nucleus to mold new neurons (Applicants Bonev, Ph.D., Boyan ;  Götz, Magdalena )
• Activity-dependent gene expression in male and female neurons: 3D genome architecture, transcription and chromatin mechanisms (Applicant Heard, Ph.D., Edith )
• Algorithms for inferring haplotype-specific chromatin contact maps in cancer using Genome Architecture Mapping (Applicant Schwarz, Roland )
• Architectural Rearrangements at the Xist locus during the onset of X-chromosome inactivation (Applicant Schulz, Edda )
• Assessing the functional role of cohesin and transcription in genome topology during Drosophila embryogenesis (Applicant Furlong, Ph.D., Eileen E. M. )
• Cell-state specific 3D genome architecture in heterogeneous cell populations of the brain. (Applicant Pombo, Ph.D., Ana )
• Characterization and testing of looping and non-looping enhancers (Applicant Ibrahim, Daniel Murad )
• Coordination and function of nuclear lamina and nuclear pore compartmentalisation in genome organisation during early mouse development (Applicant Torres-Padilla, Maria Elena )
• Coordination Funds (Applicant Papantonis, Argyris )
• Coordination Project for the Priority Programme "Spatial Genome Architecture in Development and Disease (Applicant Mundlos, Stefan )
• Deciphering the function of Nuclear Speckles in 3D genome architecture (Applicant Aktas, Ph.D., Tugce )
• Deregulation of 3D genome structure in models of memory and learning disability (Applicant Pombo, Ph.D., Ana )
• Determining TADs as conserved regulatory units in vertebrate heart development (Applicant Ibrahim, Daniel Murad )
• Dissecting structural and functional cooperation between cis-regulatory elements in higher-order chromatin structures (Applicant Oudelaar, A. Marieke )
• Dissecting the role of chromosome genome organization in chromosome fragility and the formation of leukemia driving translocations. (Applicant Roukos, Vassilis )
• Endogenous retroviruses in genome organization during early embryogenesis (Applicant Hnisz, Ph.D., Denes )
• Evolution of 3D chromatin architecture: The role of CTCF across taxa (Applicants Lupiáñez García, Ph.D., Darío Jesús ;  Zinzen, Robert Patrick )
• Exploring the contribution of RNA polymerases to mammalian 3D genome architecture (Applicant Papantonis, Argyris )
• From fibers to the sea of nuclesomes: Computer simulations of the regulation of the spatial structure of Mbp chromatin domains in the nucleus (Applicant Wedemann, Gero )
• Functional Characterization and Heterogeneity of the DLBCL and AML 3D Genomes (Applicant Vaquerizas, Juan M. )
• Functional organization of co-regulated RNA polymerase II nuclear subcompartments activated by TNFα or TGFβ (Applicant Rippe, Karsten )
• Measuring genome organization during stem cell differentiation with super-resolution microscopy (Applicants Harz, Hartmann ;  Leonhardt, Heinrich )
• Modeling embryonal neuroblastoma tumorigenesis by activation of chromosomal 3D super enhancer interactions and genomic instability (Applicants Herrmann, Carl ;  Westermann, Frank )
• Modification of 3D genome architecture and gene expression at the Fgf8 locus by transposable elements and structural variations (Applicant Mundlos, Stefan )
• Nuclear landscape of HIV-1 integration in microglia - unexplored HIV-1 reservoirs (Applicants Herrmann, Carl ;  Lusic, Ph.D., Marina )
• Nuclear pore complex proteins-directed 3D nuclear architecture in neural development and disease (Applicants Poetsch, Anna ;  Toda, Ph.D., Tomohisa )
• Position effects in the 3D genome as the cause of neurodevelopmental disorders (Applicant Spielmann, Malte )
• Regulation of mammalian genome architecture and mobility (Applicants Cardoso, Maria Cristina ;  Rohr, Karl )
• Revealing the function of heterochromatin spatial organization in response to early-life environmental challenges in C. elegans (Applicant Cabianca, Ph.D., Daphne Selvaggia )
• Single molecule imaging of architectural proteins during zebrafish embryo development (Applicant Gebhardt, Christof )
• Spatial organization of transcribed genes in mammalian cells (Applicant Solovei, Ph.D., Irina )
• Structuring the genome through phase-separated transcriptional condensates (Applicant Hnisz, Ph.D., Denes )
• Understanding how changes in spatial chromatin organization cause defective gene expression in acute myeloid leukemia with cohesin mutations. (Applicant Gebhard, Ph.D., Claudia )
• Understanding the interplay between transcription and cohesin-mediated loop extrusion at the single molecule level (Applicant Kim, Ph.D., Eugene )
• Visualizing nanoscale 3D genome architecture and transcriptional state during cell fate specification in the early mouse embryo (Applicant Ellenberg, Jan )

• Spokesperson: Professor Dr. Argyris Papantonis