The chromatinized genome regulates transcription by posing physical barriers to the activity of RNA Polymerase II and the binding of transcription factors (TFs). Access to gene promoters is attained via a complex interplay between TFs, transcriptional co-regulators (both activators and repressors) which recognize and alter histone modifications, and chromatin remodelers. The Thomä lab utilizes a combination of structural techniques, biochemistry, and functional assays to dissect how the position and orientation of specific DNA motifs on nucleosomes control TF binding.
We have investigated how TFs such as OCT4-SOX2 (Michael, Grand, Isbel et al., Science, 2020), MYC-MAX, and CLOCK-BMAL1 (Michael et al., Nature, 2023) engage nucleosomes in different positions. We have shown that these TFs trigger DNA distortions by recognizing partial motifs or DNA release and make TF and site-specific histone contacts. Ongoing work aims to understand how TF chromatin occupancy influences upstream and downstream transcription regulation pathways. As a next logical step, the lab will focus on how the complexes between nucleosomes and transcription are decoded by downstream cofactors and the transcriptional machinery.