Mechanisms controlling binding site selection of ETS family transcription factors

• Applicant: Professor Dr. Michael Rehli
• Subject Area: Hematology, Oncology ; Biochemistry
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457486890

The ETS family transcription factor (TF) PU.1 is a prototypic master regulator of the hematopoietic compartment. It has been implicated in leukemia and is required for the normal generation of several blood cell lineages. The mechanisms controlling PU.1 access to and selection of its binding sites in competition with nucleosomes and other chromatin associated proteins is only partially understood, but clearly fundamental for hematopoiesis. In a previous DFG-funded project, we systematically analyzed DNA-binding in vitro and genome-wide in vivo across many different cell types with native or ectopic PU.1 expression. We found that in vitro, PU.1 binding to DNA is subject to both epigenetic and chromatin constraints. However, in vivo, the ectopic, transient induction of PU.1 lead to the extensive remodeling of chromatin (on nucleosome, but not on genome level) and redistribution of partner TFs. Both phenomena required PU.1’s N-terminal acidic activation domain and its ability to recruit SWI/SNF remodeling complexes. The current application aims at continuing this work to further characterize chromatin and remodeler interactions of PU.1 and to determine their functional relevance in hematopoiesis, also in comparison to other ETS family factors. The results of this project will advance our knowledge of a process that is fundamental to gene regulation in hematopoiesis and in general. In a broader sense and given the role of ETS-factors in leukemia, our findings may also relate to mechanisms of leukemogenesis

• DFG Programme: Research Grants