The epigenetic landscape modulates pioneer transcription factor binding

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Packaging of DNA in the nucleosome can physically block the access of transcription factors that regulate gene expression to their binding sites. Restricting access to DNA is an integral part of how transcription is regulated. However, pioneer transcription factors can bind to their target piece of DNA even within compacted chromatin and are also known to promote the binding of other transcription factors.

Among the pioneering transcription factors are the so-called Yamanaka factors which include Oct4 and are used to induce pluripotency (the ability to give rise to different cell types). It was not clear how the pioneer transcription factors access tightly coiled DNA. To better understand the process, St. Jude scientists used cryo-electron microscopy (cryo-EM) and biochemistry to investigate how Oct4 interacts with nucleosomes.

“Building on previous work to understand the dynamic behavior of nucleosomes, we wanted to understand how other factors might use those dynamic changes to access chromatin,” said corresponding author Mario Halic, Ph.D., Department of Structural Biology at St Jude. “Oct4 didn’t bind where we anticipated it could, instead of binding inside the nucleosome, we found that it did bind a bit outside.”

“One of the main findings is that epigenetic modifications can affect transcription factor binding and cooperativity,” Halic added. “The existing epigenetic state of chromatin may determine how transcription factors will cooperatively bind to chromatin.”

The epigenetic impact

The results show that the first binding of the Oct4 molecule “fixes” the nucleosome in a position that increases the exposure of other binding sites, thus promoting the binding of additional transcription factors and explaining transcription factor cooperativity. the interactions promote chromatin opening and influence cooperativity. His work also showed that modifications to histone H3K27 affect DNA positioning by October 4. These findings explain how the epigenetic landscape can regulate Oct4 activity to ensure proper cellular programming.

In particular, the researchers used endogenous human DNA sequences instead of artificial sequences to assemble their nucleosomes. This allowed them to study the dynamic nature of the nucleosome, even though it was more difficult to work with.

“In this work, we used actual genomic DNA sequences to study transcription factors in the context in which they function,” said first author Kalyan Sinha, Ph.D., St. Jude Department of Structural Biology. “This strategy allowed us to discover that the first Oct4 binding event positions nucleosomal DNA in a way that allows for the cooperative binding of additional Oct4 molecules to internal sites. Furthermore, we observed exciting interactions with histone tails and have seen that modifications of histones can alter those interactions. Together, these findings provide new insights into the pioneering activity of Oct4.”

“Histone modifications affect how DNA is positioned and how transcription factors can cooperatively bind,” Sinha added, “meaning that in cells, if you have the same DNA sequence, different modifications Epigenetics may result in different combinatorial effects on transcription factor binding.”