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.Cell fate control represents the most extreme form of gene regulation. Genes specific to the function of a particular type of cell may be antagonistic to the function of another type of cell, so nature has evolved diverse regulatory mechanisms to ensure stable patterns of gene activation and repression. In prokaryotes, self-sustaining regulatory networks of transcription factors bound to DNA can be sufficient to regulate gene activation and repression (Ptashne 2011). In eukaryotes, ;200-base-pair (bp) segments of the genome are wound nearly twice around an octamer of the four core histones to form nucleosomes, providing steric constraints on how transcription factors can bind DNA (Kornberg and Lorch 1999). As described below, pioneer transcription factors have the special property of being able to overcome such constraints, enabling the factors to engage closed chromatin that is not accessible by other types of transcription factors (Fig. 1). However, further higher-order packaging of nucleosomes into heterochromatin can occlude access to DNA altogether, presenting an additional barrier to cell fate conversion (Fig. 1). This review focuses on the most recent studies of pioneer factors in cell programming and reprogramming, how pioneer factors have special chromatinbinding properties, and facilitators and impediments to chromatin binding. We project that such knowledge will greatly aid future efforts to change the fates of cells at will for research, diagnostic, and therapeutic purposes.

Stable Binding of the Conserved Transcription Factor Grainy Head to its Target Genes ThroughoutDrosophila melanogasterDevelopment

“…These changes in binding site occupancy by sequence-specific transcription factors are regulated largely through alterations in chromatin structure that modulate the accessible regions of the genome Li et al 2011). Nonetheless, factors that act at the top of gene regulatory networks may have pioneering activity, marking cis-regulatory regions, and remaining bound to DNA in multiple developmental contexts (Spitz and Furlong 2012;Iwafuchi-Doi and Zaret 2014;Slattery et al 2014). To begin to explore the mechanisms by which widely expressed transcription factors can regulate a variety of developmental processes, we focused on the deeply conserved transcription factor Grainy head (Grh), which is a master regulator of epithelial cell fate.…”

Signatures of DNA target selectivity by ETS transcription factors

“…The starkly different kinetic profiles establish that interfacial hydration defines different mechanisms of target recognition by the two ETS homologs. In addition, the persistence of the PU.1/DNA complex against dissociation is consistent with PU.1 as a strong pioneer transcription factor, 63 by anchoring target genes in chromatin during recruitment of other transcription factors and remodeling proteins (such as histone acetyltransferases). 64 Currently, the pioneer status of Ets-1 is controversial: Although it appears to co-localize with nucleosomes in enhancer regions in developing thymocytes, 52 it does not exhibit functional pioneer activity in a defined reporter assay.…”

Bioinformatic and Genomic Analyses of Cellular Reprogramming and Direct Lineage Conversion

“…Studying the epigenetics of iPS cells is not limited to changes during reprogramming, but also that of the starting cells themselves. While the reprogramming factors are mostly able to bind to chromatinized templates [43,106], genomic regions in the starting cells that are heavily marked with H3K9me3, a mark of heterochromatin, can indeed block the function of the Oct4, Sox2, and Klf4 and thereby inhibit reprogramming [79]. In contrast, broad domains of H3K4me3 can enhance transcriptional consistency and are established at pluripotency genes during reprogramming [5].…”