Resolving the mechanisms of gene regulation by SMC protein complexes

• Applicant: Professor Dr. Christian H. Häring
• Subject Area: General Genetics and Functional Genome Biology ; Biochemistry ; Structural Biology ; Cell Biology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 427551015

Whether and how the three-dimensional organization of the genome impinges on gene regulation is a major unresolved question of cell biology. Recent studies have revealed that protein complexes of the Structural Maintenance of Chromosome (SMC) family are the key players in defining higher-order chromatin architecture and most likely act by extruding large loops of DNA. In the interdisciplinary Work Program outlined in this proposal, we aim to uncover the mechanisms of action of the genetically well-characterized Caenorhabditis elegans Dosage Compensation Complex (DCC) as a paradigm of SMC-mediated gene regulation. Using a state-of-the-art combination of integrated structural biology and biochemistry approaches, we will reconstitute the assembly of the DCC in vitro and resolve the mechanisms that underlie complex formation and DNA binding to near-atomic resolution. In parallel, we will reveal how the complex is specifically targeted to X chromosomes in hermaphrodite nematodes and investigate its effect on chromosome architecture and transcriptional regulation. Together, these complementary experimental approaches have the potential to provide fundamentally new insights into the general principles behind targeting of SMC protein complexes to specific chromosomal addresses, their migration along the chromatin fiber and their impact on chromatin topology. Revealing how higher order-chromosome architecture impacts on gene expression will ultimately be essential to understand how these mechanisms are maintained in human health and altered in disease.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Partner Organisation: Schweizerischer Nationalfonds (SNF)
• Cooperation Partner: Professor Peter Meister, Ph.D.