All cells in your body contain the same genetic information in the form of genes encoded within DNA. Yet, cells use this information in different ways so that the activities of individual genes within that DNA can vary from cell to cell. This allows identical cells to become different to each other and to adapt to changing circumstances.

A group of proteins called transcription factors control the activity of certain genes by binding to specific sites on DNA. However, this isn’t a straightforward process because DNA in human and other animal cells is usually associated with structures called nucleosomes that can block access to the DNA. Pioneer transcription factors, such as OCT4, are a specific group of transcription factors that can attach to DNA in spite of the nucleosomes, but it’s not clear how this is possible. Once pioneer transcription factors attach to DNA they can help other transcription factors to bind alongside them.

King et al. studied OCT4 in stem cells from mouse embryos to investigate how it is able to act as a pioneer transcription factor and control gene activity. The experiments show that several other transcription factors lose the ability to bind to DNA when OCT4 is absent. This leads to widespread changes in gene activity in the cells, which seems to be due to other transcription factors being unable to get past the nucleosomes to attach to the DNA.

Further experiments showed that OCT4 needs a protein called BRG1 in order to act as a pioneer transcription factor. BRG1 is an enzyme that is able to move and remove (remodel) nucleosomes attached to DNA, suggesting that normal transcription factor binding requires this activity. The next challenge is to investigate whether BRG1, or similar enzymes, are also needed by other pioneer transcription factors that are required for normal gene activity and cell identity. This will be important because many enzymes that remodel nucleosomes are disrupted in human diseases like cancer where cells lose their normal identity.

Transcription factors read DNA-encoded information to control gene transcription and define the complement of proteins a cell can produce. They achieve this by physically binding specific DNA sequence motifs in gene regulatory elements that ultimately control how RNA polymerases engage with and transcribe genes (Spitz and Furlong, 2012; Voss and Hager, 2014). In prokaryotes, transcription factors tend to function as self-contained units that recognize extended DNA sequences with high specificity and affinity (Wunderlich and Mirny, 2009). Therefore, simple sequence-based principles appear to dictate their binding in the genome. In contrast, transcription factors in higher eukaryotes recognize shorter DNA sequences and often interface with other DNA-binding transcription factors in a combinatorial manner to achieve affinity and specificity (Wunderlich and Mirny, 2009; Villar et al., 2014). In addition to the widespread requirement for combinatorial DNA binding, eukaryotic transcription factors are also confronted with the added complexity that eukaryotic DNA is wrapped around histones to form nucleosomes and chromatin (Kornberg and Lorch, 1999). The association of DNA with nucleosomes can therefore compete with DNA-binding transcription factors, limiting their ability to engage with the genome (Spitz and Furlong, 2012; Voss and Hager, 2014). Indeed, in many cases transcription factor binding appears to require pre-existing chromatin accessibility (Guertin and Lis, 2010; Biddie et al., 2011; John et al., 2011).

This chromatin barrier therefore poses a significant challenge in establishing new gene regulatory elements when cells differentiate during development. Therefore, to overcome this obstacle, cells have evolved a specialised set of transcription factors that are able to recognise their cognate motifs even when nucleosomes are present (Zaret and Carroll, 2011). This is exemplified by the forkhead box A1 (FoxA1) transcription factor, which binds to and de-compacts nucleosomal DNA in vitro (Cirillo et al., 2002) and in vivo (Holmqvist et al., 2005; Lupien et al., 2008; Iwafuchi-Doi et al., 2016). Based on this type of activity, factors like FoxA1 have been called ‘pioneer’ transcription factors as they appear to play a primary role in recognizing and shaping how new gene regulatory elements are established in previously inaccessible chromatin (Magnani et al., 2011; Zaret and Carroll, 2011). Once bound to their target sites, pioneer transcription factors appear to create accessible chromatin (Raposo et al., 2015; Schulz et al., 2015) that supports the recruitment of non-pioneer transcription factors and the formation of functional gene regulatory elements (Theodorou et al., 2013; Wapinski et al., 2013; Foo et al., 2014; Xu et al., 2014; Schulz et al., 2015). These unique features of pioneer transcription factors allow them to function as master regulators that underpin developmental transitions, cellular reprogramming, and responses to cellular signalling events.

The capacity of pioneer transcription factors to destabilise or reposition nucleosomes to facilitate chromatin accessibility at their target sites appears to be an essential feature of their activity. Initially, it was proposed that pioneer factors might achieve this by interacting specifically with nucleosomes to alter chromatin structure. For example, FoxA1 and FoxO1 structurally resemble histone H1, which has been proposed to lead to displacement of H1 and destabilisation of neighbouring nucleosomes (Cirillo et al., 2002; Hatta and Cirillo, 2007). Alternatively, it has been proposed that ATP-dependent chromatin remodellers may be required to assist pioneer transcription factors in establishing accessible chromatin (Hu et al., 2011; Marathe et al., 2013; Ceballos-Chávez et al., 2015; Swinstead et al., 2016). Nevertheless, for most pioneer transcription factors there remains limited understanding of the mechanisms by which they translate their binding within inaccessible and nucleosome-occluded chromatin into effects on chromatin structure that support additional transcription factor binding and gene regulation.

One paradigm that has been used to study pioneer transcription factor function is the cellular reprogramming of somatic cells into induced pluripotent stem cells (iPSC) by the Yamanaka transcription factors (OCT4, SOX2, KLF4, and c-MYC) (Takahashi and Yamanaka, 2006). With the exception of c-MYC, these transcription factors are proposed to act as pioneers during cellular reprogramming and can bind their targets sites even when they are occupied by nucleosomes (Soufi et al., 2012, 2015; Chen et al., 2016). It is thought that this pioneering activity may then pave the way for nucleosome displacement and further transcription factor binding that establishes functional regulatory elements (You et al., 2011; Shakya et al., 2015; Simandi et al., 2016). While it is clear that these transcription factors have the capacity to engage with previously inaccessible regions of chromatin during iPSC reprogramming, it is unknown whether additional mechanisms are required to transition these initial engagement events into functionally mature transcription factor binding as part of the pluripotency-associated regulatory network.

To begin addressing this fundamental gap in our understanding, we have used mouse embryonic stem cells, which exist in an established pluripotent state, as a model system to dissect how the core pluripotency transcription factor OCT4 engages with target sites inside cells. In doing so we discover that OCT4 occupies sites that would otherwise be inaccessible and is required to shape the occupancy of additional pluripotency transcription factors. OCT4 achieves this by recruiting the chromatin remodelling factor BRG1 to support not only its own binding but also to stabilize further transcription factor binding events required to support pluripotency-associated gene regulation. This reveals that although OCT4 can engage with its target sites in inaccessible chromatin, the recruitment of a chromatin remodelling enzyme is a fundamental step in pluripotency transcription factor binding and gene expression. Intriguingly, OCT4-bound regulatory sites that require BRG1 are activated more slowly in response to cellular reprogramming and later during early development. Together these observations reveal that the capacity of OCT4 to cooperate with a chromatin remodeller is a key feature of its pioneering activity, and this is required to mature transcription factor binding and create functional gene regulatory elements.

Although the capacity of pioneer transcription factors to bind their sequence motifs in chromatinized DNA has been studied in detail, the mechanisms that support how individual pioneer transcription factors function to create accessible chromatin and shape regulatory element function remain poorly defined. Through studying the pioneer transcription factor OCT4, we establish that OCT4 binds to sites in mouse ESCs that would otherwise be inaccessible to shape chromatin accessibility and transcription factor binding (Figures 1 and 2). This suggests that the pioneering activities of OCT4 are required not only during reprogramming, but also in the established pluripotent state. Interestingly, chromatin accessibility formed at OCT4 binding sites relies on the chromatin remodelling factor BRG1 (Figure 3) which is recruited to these sites by OCT4 (Figure 4). The occupancy of BRG1 is then required to support efficient OCT4, SOX2 and NANOG binding and normal expression of the pluripotency-associated transcriptome (Figure 5). Importantly, this reliance on BRG1 reflects OCT4 binding dynamics during cellular reprogramming and early mouse development (Figure 6). Together these observations reveal a distinct requirement for the chromatin remodelling factor BRG1 in shaping the activity of the pioneer transcription factor OCT4 and regulating the pluripotency network in embryonic stem cells.

Pioneer transcription factors play very defined roles in shaping gene expression in response to cellular reprogramming (Soufi et al., 2012; Raposo et al., 2015; Boller et al., 2016; Chen et al., 2016), developmental stimuli, and environmental cues (Hu et al., 2011; Wu et al., 2011; Ballaré et al., 2013; Schulz et al., 2015). While considerable effort has focused on characterizing the chromatin binding activity of pioneer transcription factors, both in vitro and in vivo, the mechanisms by which individual pioneer transcription factors shape chromatin structure and support further transcription factor engagement in vivo have remained poorly understood. Our examination of OCT4 binding now provides a potential rationalization for how this pioneer transcription factor functions to form gene regulatory elements in mouse ESCs. A requirement of this process is OCT4's ability to engage with sequences in inaccessible chromatin presumably through its capacity to bind nucleosomal DNA (Figure 1; Soufi et al., 2012, 2015), suggesting that OCT4 may be able to dynamically sample its target sites throughout the genome. However, cooperation with BRG1 appears to be required for more stable OCT4 binding (Figure 5). This could be achieved through the chromatin remodelling activity of BRG1 creating transiently accessible DNA that facilitates further OCT4 binding and ultimately more stable cooperative binding with other transcription factors like SOX2 and NANOG. This general model is consistent with previous experiments that showed enhanced OCT4 binding during OCT4-SOX2-KLF4 reprogramming when BRG1 was included in the reprogramming cocktail (Singhal et al., 2010) and is in agreement with our observation that BRG1 is required for normal chromatin accessibility and OCT4 binding at otherwise inaccessible and inactive regulatory elements.

The capacity of OCT4 to recognise its target motifs in inaccessible chromatin may allow it to dynamically sample its complement of binding sites in the genome. However, like many transcription factors, OCT4 only binds stably to a subset of these sites. Our genome-wide analyses indicate that BRG1 and transcription factor co-binding events appear to be essential in stabilizing OCT4 binding and the functional maturation of OCT4-dependent regulatory elements in ESCs. Based on these observations, one would predict that co-binding transcription factors might play a central role in shaping where OCT4 stably engages with the genome in different cell types. In fitting with this possibility, when ESCs are transitioned into epiblast-like cells (EpiLCs), OCT4 stably associates with a new set of previously inaccessible sites in a manner that appears to rely on co-binding of the EpiLC-specific transcription factor OTX2 (Buecker et al., 2014; Yang et al., 2014). In the context of these and other observations, it is tempting to speculate that OCT4, through its association with BRG1, is exploited as a dynamic pioneering and chromatin remodelling module by distinct co-binding transcription factors to support the formation of cell type-specific regulatory elements during developmental transitions and reprogramming. In agreement with these general ideas, OCT4 appears to be the only Yamanaka transcription factor that cannot be substituted for in iPSC reprogramming experiments, suggesting its pioneering activity is fundamental in establishing and maintaining the pluripotency network in concert with SOX2, KLF4 and c-Myc (Nakagawa et al., 2008; Sterneckert et al., 2012), perhaps due to its cooperation with BRG1 (Singhal et al., 2010; Esch et al., 2013). This central requirement in reprogramming is also consistent with our observations that OCT4 plays an essential and BRG1-dependent role in shaping the binding of other pluripotency-associated factors at thousands of distal regulatory elements in ESCs.

One of the central features of pioneer transcription factors is their ability to alter local chromatin structure, and this is closely linked to their capacity to support further transcription factor binding and enable the functional maturation of distal regulatory elements. Yet, in most instances the defined molecular mechanisms that support these activities have remained undetermined. While some pioneer factors, such as FoxA1, can stably bind their target sites and directly alter nucleosomal structure through steric disruption of histone:DNA contacts (Cirillo et al., 2002; Hatta and Cirillo, 2007; Iwafuchi-Doi et al., 2016), the extent to which other pioneer factors might exploit such a mechanism has yet to be fully addressed. In the case of OCT4, our observations establish that its capacity to support transcription factor binding and chromatin accessibility requires the chromatin remodeller BRG1. This suggests that unlike FoxA1, OCT4 does not have an intrinsic chromatin opening activity, but requires cooperation with BRG1 to achieve this. Indeed, our work on OCT4 is generally consistent with and supported by recent work studying the pioneer factor GATA3 which appears to have similar dependency on BRG1 in creating accessible chromatin (Takaku et al., 2016). Furthermore, chromatin remodelling activity has been widely implicated in shaping nucleosome positioning and chromatin accessibility at target sites bound by other pioneer transcription factors (Hu et al., 2011; Sanalkumar et al., 2014; Ceballos-Chávez et al., 2015; Hainer and Fazzio, 2015). Together, these observations suggest that many pioneer transcription factors may rely on chromatin remodelling as a key step in supporting transcription factor binding and/or co-binding events in a manner broadly consistent with the previously proposed assisted loading model for transcription factor binding (Voss and Hager, 2014; Swinstead et al., 2016). In the context of this model, the dynamic binding, release and re-binding of transcription factors would help to maintain and stabilise transcription factor binding events, but critically, chromatin remodellers appear to be important in many cases to achieve this (reviewed recently in Swinstead et al., 2016). Clearly more work is required to understand the extent to which pioneer transcription factors use chromatin remodellers to support their pioneering activities. However, in the case of the developmental pioneer transcription factors OCT4 and GATA3, chromatin remodellers act as key component necessary for the formation and function of gene regulatory elements. These emerging observations suggest that chromatin remodelling could function as a central feature of pioneer transcription factor activity during the formation and maintenance of cell type-specific transcriptional programs during development and reprogramming.

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Author details

1. Hamish W King

   Department of Biochemistry, University of Oxford, Oxford, United Kingdom

   Contribution

   HWK, Conceptualization, Data curation, Software, Formal analysis, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0001-5972-8926

2. Robert J Klose

   Department of Biochemistry, University of Oxford, Oxford, United Kingdom

   Contribution

   RJK, Supervision, Funding acquisition, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   rob.klose@bioch.ox.ac.uk

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-8726-7888

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