Mechanisms controlling common and cell type-specific DNA binding of the master regulator PU.1

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Cell type-specific gene regulation is controlled by the combination of specific transcription factors as well as epigenetic mechanisms that control the structure and accessibility of DNA in chromatin. Master regulators (also called "pioneering factors") like the myeloid and B cell-specific transcription factor PU.1 play key roles in lineage differentiation and specification and share a unique ability to overcome chromatin restriction and to open up chromatin for other factors. The specific features of master regulators (or transcription factors in general) that enable them to access DNA in chromatin as well as the general rules for DNA binding (only a minor fraction of recognition sites is usually occupied) remain to be defined. Based on recent own and published evidence, we hypothesize that the binding of the master regulator PU.1 to genomic DNA is controlled by a combination of sequence motif affinity, cooperativeness between neighboring binding sites and the engagement of chromatin remodeling complexes. Using computational, molecular as well as biochemical approaches, this project intends to study the rules and properties for PU.1 binding to DNA in vitro and in vivo to uncover the underlying principles. This work will reveal fundamental insights into the biology of the master regulator PU.1, which are likely applicable to other systems.