Mechanisms of OCT4-SOX2 motif readout on nucleosomes
Alicia K. Michael, Ralph S. Grand, Luke Isbel, Simone Cavadini, Zuzanna Kozicka, Georg Kempf, R.D. Bunker, Andreas D. Schenk, Alexandra Graff-Meyer, G.R. Pathare, Joscha Weiss, S. Matsumoto, Lukas Burger, Dirk Schübeler, Nicolas H. Thomä
Abstract
Transcription factors (TFs) regulate gene expression through chromatin where nucleosomes restrict DNA access. To study how TFs bind nucleosome-occupied motifs, we focused on the reprogramming factors OCT4 and SOX2 in mouse embryonic stem cells. We determined TF engagement throughout a nucleosome at base-pair resolution in vitro, enabling structure determination by cryo-electron microscopy at two preferred positions. Depending on motif location, OCT4 and SOX2 differentially distort nucleosomal DNA. At one position, OCT4-SOX2 removes DNA from histone H2A and histone H3; however, at an inverted motif, the TFs only induce local DNA distortions. OCT4 uses one of its two DNA-binding domains to engage DNA in both structures, reading out a partial motif. These findings explain site-specific nucleosome engagement by the pluripotency factors OCT4 and SOX2, and they reveal how TFs distort nucleosomes to access chromatinized motifs.