Interplay between cohesin and the transcription factor PU.1 in regulating distal enhancer function

• Applicant: Professor Dr. Michael Rehli
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 557614137

In non-dividing cells, cohesin organizes nuclear genome architecture by creating chromatin loops. When loaded onto chromatin, it actively moves along two strands of chromatin in a dynamic process called loop extrusion, which can connect regulatory or structural elements and regulate transcription. While mutations in cohesin components are associated with diseases such as leukemia, the effects of acute cohesin depletion in cell lines cause only mild transcriptional changes, and we still don’t understand, where and when cohesin is required for proper gene regulation. In preliminary, unpublished work we observed that the hematopoietic transcription factor PU.1 rapidly recruits cohesin to de-novo created binding sites, and that the presence of cohesin is required for a significant fraction of its target genes. In this application we propose to combine our established model of acute transcription factor induction with acute degradation of cohesin to systematically unravel the direct interplay of de novo chromatin remodeling, loop extrusion and transcription. The proposed project will reveal interesting insights into the biology of PU.1 and distal cis-regulatory elements in general (e.g. how they interact with their target genes, and when cohesin is important for this interaction). Finally, it may also help to explain the mechanisms of leukemogenesis in cohesin mutated acute myeloid leukemia.

• DFG Programme: Research Grants