A new study from scientists at EPFL's Institute of Bioengineering shows how transcription factors dynamically regulate chromatin accessibility across the cell cycle of stem cells.



In a paper published recently in eLife, scientists from the lab of David Suter at EPFL, in collaboration with the lab of Bart Deplancke, have examined the way so-called "pioneer" transcription factors, which bind and induce the opening of hard-to-reach chromatin regions that are shielded by the nucleosome. As a consequence, pioneer transcription factors are extensively studied in the context of cellular differentiation and reprogramming.

The study examines how two pioneer transcription factors, OCT4 and SOX2, control chromatin accessibility in mouse embryonic stem cells. The two factors are important because they join together into a complex that binds thousands of sites across the genome. What this means is that they have far-reaching effects on the cell's genes; for example, both have been shown to be indispensable for the self-renewal of embryonic stem cells.

But, as the authors write, “the function of pioneer activity in self-renewing cell divisions and across the cell cycle is poorly understood.” Their study found that OCT4 and SOX2 actually operate in “a largely independent manner”; in fact, it appears that when one factor favors the DNA binding of the other, this is actually mostly mediated indirectly through modulation of DNA accessibility to the transcription machinery.

Further, the study found that OCT4 is absolutely necessary for two main aspects of the stem cell's life: re-establishing itself after mitosis, and constantly maintaining chromatin accessibility of key regulatory regions during interphase. The authors write: “Our study sheds light on the constant pioneer activity required to maintain the dynamic pluripotency regulatory landscape in an accessible state.”

Pioneer transcription factors (TFs) typically require hours to days to open chromatin and make DNA accessible in the context of cell differentiation. In contrast, the pioneering action of OCT4 together with the chromatin remodeling complex BAF is highly dynamic and operates on much shorter time scales. Credit: D. Suter (EPFL)