Deciphering the function of Nuclear Speckles in 3D genome architecture

• Applicant: Dr. Tugce Aktas, Ph.D.
• Subject Area: General Genetics and Functional Genome Biology ; Biochemistry ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 507866755

The nucleus of human cells is compartmentalized into functional DNA and protein assemblies that execute essential biological processes in a tightly controlled manner. Biomolecular condensates are membraneless bodies with essential roles in compartmentalizing biochemical reactions in cells. Nuclear speckles (NS) are amongst the most prominent condensates in the human nucleus and are implicated to have a role in regulating transcription, RNA processing and export. Moreover, the proximity of a gene locus to the NS in three dimensional space correlates with high transcription rates from this locus. However, the majority of these connections between NS and gene expression regulation originate from correlative studies, especially in the absence of direct evidence from an NS-absent cell state. We identified two evolutionarily conserved, large and disordered proteins, SON and SRRM2, as the essential proteins for NS formation. This finding does not only allow us to investigate the function of NS in humans, but also opens up new possibilities for studying the evolution of NS and of its functions. The main goal of the project proposed here is to bring two compartmentalisation processes in the nucleus —chromatin topology and biomolecular condensates— together using nuclear speckles as a model. We will investigate the role of NS in nuclear architecture and establish connections between its role in RNA processing and nuclear architecture. This work will be further expanded into fruit flies in order to find evolutionary parallels between gene expression programs and the nuclear architecture. Since loss of function mutations of SON were identified in human patients with intellectual disability and developmental delay, the proposed project will have the possibility to provide more mechanistic understanding into the disease phenotype.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2202: Spatial Genome Architecture in Development and Disease