How transcription factors recognize binding motifs on chromatin

From left to right: Luke Isbel, Alicia K. Michael, Ralph S. Grand

From left to right: Luke Isbel, Alicia K. Michael, Ralph S. Grand

In a video (5’35’’) combining interviews and figures, the team behind the latest collaboration from the Thomä and Schübeler labs - Alicia Michael, Ralph Grand and Luke Isbel - explain how they developed an assay identifying where the preferable sites for the transcription factor-DNA binding motif on the nucleosome were, so that they could build transcription factor-nucleosome complexes.

The DNA in our cells is wrapped around histone proteins to form nucleosomes, and then further condensed into chromatin, which helps to package the DNA in the nucleus and plays a role in the regulation of gene expression.

While it has long been known in the field of epigenetics that transcription factors must be able to find and bind to their DNA binding motifs in the context of chromatin, until now it was not known how this was happening or what this looked like.

In a video (5’35’’), the team behind the latest collaboration from the Thomä and Schübeler labs, Alicia Michael, Ralph Grand and Luke Isbel, explain how they developed an assay identifying where the preferable sites for the transcription factor DNA binding motif on the nucleosome were, so that they could build transcription factor-nucleosome complexes. This assay revealed high affinity binding sites for a pair of pioneering transcription factors, Oct4 and SOX2, and enabled the determination of cryo-EM structures of OCT4-SOX2 bound to DNA within a nucleosome. The structures reveal how, by recognizing just part of its DNA-binding motif, only a subset of OCT4’s DNA-binding domains appears to hold the DNA, while SOX2 lifts the DNA away from the surface of the nucleosome. The reserachers also proved that a partial DNA-binding motif engagement is sufficient for these factors to engage chromatin in vivo. This may indicate how the transcription factors open chromatin and allow recruitment of additional factors for DNA transcription and subsequent gene expression.

The team hopes that these techniques can be used to characterize the nucleosome-transcription factor binding relationship for other transcription factors in the future, and give further insight into how other necessary factors gather at chromatin to initiate transcription and ultimately express genes.

Original publication:
Alicia K. Michael*, Ralph S. Grand*, Luke Isbel*, Simone Cavadini, Zuzanna Kozicka, Georg Kempf, Richard D. Bunker, Andreas D. Schenk, Alexandra Graff-Meyer, Ganesh R. Pathare, Joscha Weiss, Syota Matsumoto, Lukas Burger, Dirk Schübeler and Nicolas H. Thomä. Mechanisms of OCT4-SOX2 motif readout on nucleosomes. Science (2020). abb0074
*equal contribution