Pioneer transcription factors in cell reprogramming

Abstract

A subset of eukaryotic transcription factors possesses the remarkable ability to reprogram one type of cell into another. The transcription factors that reprogram cell fate are invariably those that are crucial for the initial cell programming in embryonic development. To elicit cell programming or reprogramming, transcription factors must be able to engage genes that are developmentally silenced and inappropriate for expression in the original cell. Developmentally silenced genes are typically embedded in "closed" chromatin that is covered by nucleosomes and not hypersensitive to nuclease probes such as DNase I. Biochemical and genomic studies have shown that transcription factors with the highest reprogramming activity often have the special ability to engage their target sites on nucleosomal DNA, thus behaving as "pioneer factors" to initiate events in closed chromatin. Other reprogramming factors appear dependent on pioneer factors for engaging nucleosomes and closed chromatin. However, certain genomic domains in which nucleosomes are occluded by higher-order chromatin structures, such as in heterochromatin, are resistant to pioneer factor binding. Understanding the means by which pioneer factors can engage closed chromatin and how heterochromatin can prevent such binding promises to advance our ability to reprogram cell fates at will and is the topic of this review.

Keywords: chromatin; development; nucleosome; pioneer transcription factor; reprogramming; transdifferentiation.

Figure 1.

Initial targeting of closed chromatin by pioneer factors. The DNA-binding domain of pioneer factors allows the protein to recognize its target site on nucleosomal DNA. The initial targeting of nucleosomal DNA by pioneer factors occurs in closed, silent chromatin that lacks nuclease hypersensitivity and consistent histone modifications or other prior marks. This allows the pioneer factor to initiate reprogramming of silent genes that may be inappropriate to express in a given cell, enabling cell type conversion. Many transcription factors (nonpioneers) cannot initially target such genes but can do so coordinately with, or after, pioneer factors bind. However, certain heterochromatic regions of the genome, such as where H3K9me2 or H3K9me3 marks are deposited, are refractory to pioneer factor binding. Continuing research on how pioneer factors can target nucleosomal sites and how heterochromatic impediments can be broken down will inform ways to enhance our ability to control cell fates for biomedical purposes.

Figure 2.

Initial targeting of pioneer factor and subsequent events. (A) Pioneer transcription factors can target sites with high intrinsic nucleosome occupancy. (B) Pioneer factors initially engage nucleosomal target sites, which enable other factors (transcription factors, chromatin modifiers, and remodelers) to access the target sites. (C) Other transcription factor (TF)-binding and chromatin modifications could stabilize pioneer factor binding to the target sites.