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. 2020 Jun 26;368(6498):1460-1465.
doi: 10.1126/science.abb0074. Epub 2020 Apr 23.

Mechanisms of OCT4-SOX2 motif readout on nucleosomes

Alicia K Michael #  1 , Ralph S Grand #  1 , Luke Isbel #  1 , Simone Cavadini  1 , Zuzanna Kozicka  1   2 , Georg Kempf  1 , Richard D Bunker  1 , Andreas D Schenk  1 , Alexandra Graff-Meyer  1 , Ganesh R Pathare  1 , Joscha Weiss  1 , Syota Matsumoto  1 , Lukas Burger  1   3 , Dirk Schübeler  4   2 , Nicolas H Thomä  4
Affiliations

Mechanisms of OCT4-SOX2 motif readout on nucleosomes

Alicia K Michael et al. Science. .

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.

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