Pioneer Transcription Factors Initiating Gene Network Changes

Abstract

Pioneer transcription factors have the intrinsic biochemical ability to scan partial DNA sequence motifs that are exposed on the surface of a nucleosome and thus access silent genes that are inaccessible to other transcription factors. Pioneer factors subsequently enable other transcription factors, nucleosome remodeling complexes, and histone modifiers to engage chromatin, thereby initiating the formation of an activating or repressive regulatory sequence. Thus, pioneer factors endow the competence for fate changes in embryonic development, are essential for cellular reprogramming, and rewire gene networks in cancer cells. Recent studies with reconstituted nucleosomes in vitro and chromatin binding in vivo reveal that pioneer factors can directly perturb nucleosome structure and chromatin accessibility in different ways. This review focuses on our current understanding of the mechanisms by which pioneer factors initiate gene network changes and will ultimately contribute to our ability to control cell fates at will.

Keywords: chromatin; differentiation; gene networks; nucleosome; pioneer factor; reprogramming.

Figure 1

Actions of pioneer transcription factors. (a) The pioneer transcription factor (gold sphere) scans laterally across chromatin and targets a nucleosome. (b) The pioneer transcription factor exposes an underlying nucleosome in chromatin, displacing linker histone. (c) The pioneer transcription factor enables the binding of other transcription factors, coactivators or corepressors, and nucleosome remodelers. Green flags represent activating histone modifications; red flags represent repressive histone modifications.

Figure 2

Transcription factor DNA-binding domains (spheres) bind to nucleosomes in diverse methods, such as (a) edge binding, (b) near dyad axis, (c) around the nucleosome, (d) dyad axis, and (e) binding to both DNA gyres (153).

Figure 3

DNA-binding domain structures that enable or limit binding to nucleosomes. (a) Two different DNA-binding domain structures are shown interacting with DNA orthogonal to the long axis of the double helix. The DNA-binding domain on the left illustrates how short α-helices enable interactions that would not sterically collide with the underlying histone surface, depicted by a green line, on a nucleosome (36, 127). (b) By contrast, extended α-helices or other structures can sterically interfere with nucleosome binding. Figure adapted from Reference with permission.

Figure 4

Pioneer transcription factors perturb nucleosome structure in different ways. (a) Pioneer factor binding can facilitate the freeing of its target site from the nucleosome. (b) Binding can cause the adjacent gyre of DNA to be released from the nucleosome. (c) Binding can perturb the interaction between the histone H4 N-terminal tail and the acidic patch of the nucleosome (target of the red arrow), which normally stabilizes internucleosome interactions.