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Review
, 25 (21), 2227-41

Pioneer Transcription Factors: Establishing Competence for Gene Expression

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Review

Pioneer Transcription Factors: Establishing Competence for Gene Expression

Kenneth S Zaret et al. Genes Dev.

Abstract

Transcription factors are adaptor molecules that detect regulatory sequences in the DNA and target the assembly of protein complexes that control gene expression. Yet much of the DNA in the eukaryotic cell is in nucleosomes and thereby occluded by histones, and can be further occluded by higher-order chromatin structures and repressor complexes. Indeed, genome-wide location analyses have revealed that, for all transcription factors tested, the vast majority of potential DNA-binding sites are unoccupied, demonstrating the inaccessibility of most of the nuclear DNA. This raises the question of how target sites at silent genes become bound de novo by transcription factors, thereby initiating regulatory events in chromatin. Binding cooperativity can be sufficient for many kinds of factors to simultaneously engage a target site in chromatin and activate gene expression. However, in cases in which the binding of a series of factors is sequential in time and thus not initially cooperative, special "pioneer transcription factors" can be the first to engage target sites in chromatin. Such initial binding can passively enhance transcription by reducing the number of additional factors that are needed to bind the DNA, culminating in activation. In addition, pioneer factor binding can actively open up the local chromatin and directly make it competent for other factors to bind. Passive and active roles for the pioneer factor FoxA occur in embryonic development, steroid hormone induction, and human cancers. Herein we review the field and describe how pioneer factors may enable cellular reprogramming.

Figures

Figure 1.
Figure 1.
Properties that distinguish pioneer factors from other transcription factors. Most transcription factors cannot access their target sequences on nucleosomes or in compacted chromatin, yet can do so when binding in a highly cooperative fashion with other transcription factors. Pioneer factors can access their target sequences on nucleosomes and certain forms of compacted chromatin, although not all forms. Pioneer factor binding occurs for a stable period and precedes the binding of other transcription factors.
Figure 2.
Figure 2.
Passive and active roles for pioneer factors in endowing transcriptional competence. In the passive role, stable, prior binding of pioneer factors to a complex regulatory sequence, such as an enhancer element, reduces the number of additional factors that are needed to bind at a later time in order to create an active enhancer. Such “priming” can increase the rapidity of a transcriptional response and is seen during development and in hormonal regulation (Gualdi et al. 1996; Carroll et al. 2005). In the active role, pioneer factors can directly facilitate other factors binding to nucleosomal DNA (Cirillo and Zaret 1999) or open up the local chromatin and thereby indirectly allow other factors to bind (Cirillo et al. 2002).
Figure 3.
Figure 3.
FoxA factors possess features of linker histones and conventional transcription factors. The crystal structures of the DNA-binding domains of linker histone (Ramakrishnan et al. 1993) and FoxA3 (Clark et al. 1993) are shown side by side. The “winged helix” motif is evident in each, consisting of a helix–turn–helix motif (HTH) flanked by wings of polypeptide chain (wing 1 and wing 2) that make minor groove contacts along the long axis of the DNA. Such binding allows other proteins (e.g., core histones) to reside on the other side of the DNA. Like linker histone, the FoxA proteins move much more slowly in chromatin than most other transcription factors, as assessed by fluorescence recovery after photobleaching (FRAP) (Sekiya et al. 2009). Unlike linker histone, FoxA proteins make specific base contacts that direct target site binding and possess an N-terminal trans-activation domain (TAD) (Pani et al. 1992). Also, FoxA proteins possess a C-terminal domain that binds directly to core histone proteins and is necessary for the factor to open chromatin (Cirillo et al. 2002).
Figure 4.
Figure 4.
Optimal chromatin features for FoxA1 binding to chromatin in breast cancer cells. The figure shows features that enhance or inhibit FoxA1 binding to chromatin in the breast cancer cell line, where parameters have been investigated in detail. FoxA1 binding in turn enables binding by ER and its cofactors, leading to the stimulation of transcription of target genes under estrogen hormonal control.

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