Pioneering the developmental frontier

Abstract

Coordinated changes in gene expression allow a single fertilized oocyte to develop into a complex multi-cellular organism. These changes in expression are controlled by transcription factors that gain access to discrete cis-regulatory elements in the genome, allowing them to activate gene expression. Although nucleosomes present barriers to transcription factor occupancy, pioneer transcription factors have unique properties that allow them to bind DNA in the context of nucleosomes, define cis-regulatory elements, and facilitate the subsequent binding of additional factors that determine gene expression. In this capacity, pioneer factors act at the top of gene-regulatory networks to control developmental transitions. Developmental context also influences pioneer factor binding and activity. Here we discuss the interplay between pioneer factors and development, their role in driving developmental transitions, and the influence of the cellular environment on pioneer factor binding and activity.

Figure 1:. Pioneer factors drive developmental transitions.

Pioneer factors reprogram specialized cell types (germ cells, fibroblasts) to pluripotency (iPSC, early embryonic cells). Expression of other pioneer factors can transdifferentiate fibroblasts to additional cell types, such as neurons and can also drive differentiation from naïve (ESC) to more specialized cell types (endoderm, EpiLC). A subset of pioneer factors involved in each conversion are listed along the arrows, which indicate the direction of the conversion events. The color of the cell represents the relative degree of differentiation with dark orange being the most differentiated.

Figure 2:. Chromatin and cofactor expression modulate pioneer-factor occupancy and activity.

A. Pioneer factors (PF) bind unmarked, silent chromatin and establish regions of accessible chromatin at enhancers to allow for the subsequent binding of lineage-specific transcription factors (TF) that drive gene expression. B. Specific chromatin modifications (such as histone methylation) act as a barrier to pioneer-factor binding. Expression of enzymes that remove these marks, such as histone demethylases (HDM), enable pioneer factors to overcome this barrier, drive accessibility at enhancers and promote gene expression. C. The expression of cofactors (CoF) can stabilize pioneer-factor binding and promote genomic occupancy. TSS, transcription start site.

Figure 3:. Cooperation amongst pioneer factors during development.

A. Simultaneous binding of multiple pioneer factors may be necessary for the formation of accessible chromatin at cis-regulatory elements. For example, during reprogramming of fibroblasts to iPSCs, Oct4, Sox2, and Klf4 are required to function together to define a subset of enhancers. B. Multiple pioneer factors (Zelda, GAGA factor, CLAMP, and Odd-paired (Opa)) function sequentially to regulate early embryonic development in Drosophila. C. Sequential action of pioneer factors can define cell-type specific enhancers that maintain gene expression during differentiation. As ESCs exit naïve pluripotency and become primed EpiLCs, GRHL2 defines novel enhancers to maintain expression of a gene regulatory network necessary for defining EpiLCs.