© 2016. Published by The Company of Biologists Ltd | Development (2016) 143, 1833-1837 doi:10.1242/dev.133900
DEVELOPMENT AT A GLANCE
Cell fate control by pioneer transcription factors
Makiko Iwafuchi-Doi and Kenneth S. Zaret*
Distinct combinations of transcription factors are necessary to elicit
cell fate changes in embryonic development. Yet within each group of
fate-changing transcription factors, a subset called ‘pioneer factors’
are dominant in their ability to engage silent, unmarked chromatin and
initiate the recruitment of other factors, thereby imparting new function
to regulatory DNA sequences. Recent studies have shown that
pioneer factors are also crucial for cellular reprogramming and that
they are implicated in the marked changes in gene regulatory
networks that occur in various cancers. Here, we provide an overview
of the contexts in which pioneer factors function, how they can target
silent genes, and their limitations at regions of heterochromatin.
Understanding how pioneer factors regulate gene expression greatly
enhances our understanding of how specific developmental lineages
are established as well as how cell fates can be manipulated.
Institute for Regenerative Medicine, Department of Cell and Developmental
Biology, Perelman School of Medicine, University of Pennsylvania, 9-131 SCTR,
3400 Civic Center Blvd., Philadelphia, PA 19104-5157, USA.
*Author for correspondence ([email protected])
K.S.Z., 0000-0001-8932-3145
KEY WORDS: Cell fate control, Pioneer factors, Transcription
Introduction
A differentiated, multicellular organism is made up of diverse cell
types that are induced and maintained by cell type-specific
chromatin states and patterns of gene expression. When new cell
fates are induced during embryonic development, tissue
regeneration or cell reprogramming, regulatory transcription
factors must suppress genes specific to the original cell fate and
activate genes specific to the new cell fate. Rather than one
regulatory protein being singularly responsible for determining each
cell type, it is well established that particular combinations of
transcription factors elicit cell fate changes and maintain cell identity
(Yamamoto, 1985). But although groups of transcription factors
elicit cell fate changes, each member of a group does not function
identically in the mechanism of changing gene expression patterns.
Data derived from chromatin-binding studies in embryos,
biochemical reconstitution of chromatin in vitro, genomics, and
genetics have revealed that certain transcription factors, termed
‘pioneer factors’, have the distinct ability to target nucleosomal
DNA sites at silent genes that have not been marked for activity, and
thus initiate the process whereby a collective of regulatory proteins
DEVELOPMENT
ABSTRACT
1833
can assemble at particular sequences and activate genes specific
to a new fate. In this way, pioneer factors are fundamental to
development and reprogramming, and have even been shown to play
a role in cancer. Here and in the accompanying poster, we provide an
overview of pioneer factors by summarizing their role in cell fate
specification and conversion, as well as the molecular basis for their
activity. Understanding how pioneer factors interact with chromatin
and the limits of their activity will enhance our ability to manipulate
cell fate control for diverse research and therapeutic purposes.
The molecular basis of pioneer factor activity
Gene regulation occurs in the context of chromatin, the complex of
DNA and histone proteins that makes up the chromosomes. Within
the chromatin, cellular DNA is wrapped nearly twice around an
octamer of the four core histones to form arrays of nucleosomes.
Linker histones bind to nucleosomes and stabilize condensed,
repressive states. Chromatin can become ‘opened’ at gene
regulatory regions, which allows RNA polymerase to function.
This type of open chromatin is known as active chromatin, or
chromatin type A. After a domain becomes open, it can typically
accommodate the binding of any transcription factor and is
accompanied by ‘active’ covalent modifications of the core
histones, including histone H3 methylation on lysine 4 (H3K4me)
and H3K9 and H3K27 acetylation (The ENCODE Project
Consortium, 2011; Kharchenko et al., 2011). At promoters, these
modifications can flank a nucleosome-free region immediately
upstream of the transcription start site.
Large-scale chromatin-mapping studies have revealed that about
half of the genome in a given cell possesses vast stretches of ‘low
signal state’ chromatin that does not accumulate either active or
repressive histone modifications (Kharchenko et al., 2011; Ho et al.,
2014; Roadmap Epigenomics Consortium et al., 2015), and thus can
be considered as unprogrammed. This type of chromatin is called
low signal chromatin, or chromatin type L. Such unprogrammed
chromatin is likely to be bound non-specifically by linker histones,
which are nearly as abundant as core histones and are inherently
repressive to transcription. Although many transcription factors
cannot access target sites in the type L chromatin, pioneer factors are
indeed capable of targeting this type of chromatin (Soufi et al.,
2012; van Oevelen et al., 2015). In contrast to active and low signal
chromatin, actively repressed chromatin domains – also known as
repressed chromatin or chromatin type R – are inhibitory to the
binding of most transcription factors, including pioneer factors, and
thus strongly repress transcription. Such closed domains are
typically accompanied by repressive covalent modifications of the
core histones, including H3K9 or H3K27 methylation, although
usually type R domains do not possess both marks at the same time,
thus reflecting the different mechanisms of chromatin repression
(Ho et al., 2014; Becker et al., 2016).
A central question regarding changes in cell fate is how genes in
silent, low signal chromatin (type L) and repressed chromatin (type
R) can be accessed and activated, despite the fact that the DNA is
nucleosomal and thus inherently closed to most binding factors.
The ability to target low signal chromatin is based on the inherent
capacity of pioneer factors to recognize their target DNA
sequences on the nucleosome (Cirillo et al., 1998), either by full
or partial motif recognition. The FoxA DNA-binding domain
(DBD) possesses a ‘winged helix’ structure that resembles the
globular, nucleosomal binding domain of linker histone, binding to
the full motif on one side of a DNA helix and leaving the other
side of DNA free to bind core histones (Clark et al., 1993;
Ramakrishnan et al., 1993; Cirillo et al., 1998). In vivo genetic and
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Development (2016) 143, 1833-1837 doi:10.1242/dev.133900
in vitro biochemical studies indicate that FoxA binding displaces
linker histones from the local chromatin and keeps nucleosomes
accessible (Cirillo et al., 1998; Iwafuchi-Doi et al., 2016).
Furthermore, the C-terminal domain of FoxA can bind directly
to core histone proteins and is required for opening chromatin,
without ATP or ATP-dependent chromatin remodelers (Cirillo
et al., 2002). In contrast to the full motif recognition binding of
FoxA, some pioneer factors recognize only a partial motif. Oct3/4
(Pou5f1), Klf4 and basic helix-loop-helix type pioneer factors,
such as Ascl1, target a partial DNA sequence of their canonical
binding motifs on DNA, which is compatible with nucleosome
binding (Soufi et al., 2015). It is now possible to predict a
transcription factor’s pioneer activity by extensive computational
analysis of genomic DNA motifs and the factor’s 3D structure
(Soufi et al., 2015). In addition, pioneer factors can be identified
empirically by their ability to target nucleosomal DNA in vivo
(Soufi et al., 2015) and/or elicit an open region of chromatin
(Sherwood et al., 2014).
Despite the importance of pioneer factor binding for initiating
changes in cell fate, the process itself is insufficient to induce
changes in gene expression directly. For this to take place, pioneer
factor binding must occur cooperatively with other factors that, by
themselves, cannot initiate such events in silent chromatin. Indeed,
FoxA can recruit other activators or repressors to their target sites
(Carroll et al., 2005; Zhang et al., 2005; Sekiya and Zaret, 2007; Li
et al., 2012a; Iwafuchi-Doi et al., 2016). In Caenorhabditis elegans
development, PHA-4, a homolog of FoxA, frequently binds
promoters and recruits RNA polymerase II (Hsu et al., 2015).
Thus, the initial chromatin-binding activity of pioneer factors is
followed by the assembly of activating or repressing complexes, as
dictated by the local DNA sequence and the presence of factors that
are able to bind and further modify the chromatin.
Pioneer factors and developmental competence
The emergence of distinct cell types during embryonic
development results from an intricate and dynamic cascade of
regulatory changes in gene expression. Pioneer factors are likely to
play a role in establishing a competence for many different cell
fates, and indeed have already been shown to be fundamental in
many developmental contexts, such as Pax7 for pituitary
melanotrope development and PU.1 (Spi1) for myeloid and
lymphoid development (summarized by Iwafuchi-Doi and Zaret,
2014). In Drosophila embryos, the maternal transcription factor
Zelda (Vielfaltig – FlyBase) plays a primary role in zygotic genome
activation following fertilization (Liang et al., 2008). Zelda is
present in nuclei earlier than other master regulators, such as Bicoid
and Dorsal, and locally opens inactive regulatory regions to allow
other transcription factors to bind (Li et al., 2014; Schulz et al.,
2015; Sun et al., 2015). Similarly, maternal Class V POU factors (e.
g. Oct3/4 and Pou5f3) and SoxB1 factors (e.g. Sox2 and Sox19) are
primary regulators of zygotic genome activation in mouse (Foygel
et al., 2008; Pan and Schultz, 2011) and zebrafish (Lee et al., 2013;
Leichsenring et al., 2013).
The TALE family of homeodomain transcription factors,
including pre-B cell leukemia homeobox (Pbx) and Meis
homebox, are important co-factors of Hox proteins. They engage
the hoxb1a promoter during early zebrafish embryogenesis and
recruit chromatin-modifying enzymes and RNA polymerase II to
establish a poised state. Hoxb1b is then recruited and activates the
hoxb1a promoter at a later stage (Choe et al., 2014). A recent study
showed that Hoxa2 is recruited to a subset of sites that are pre-bound
by Meis, which specifies the second branchial arches (Amin et al.,
DEVELOPMENT
DEVELOPMENT AT A GLANCE
2015). Pbx also acts as a pioneer factor to enable the action of MyoD
in specifying muscle fate (Berkes et al., 2004).
Pioneer factors FoxA and GATA
As a paradigm, the pioneer factors FoxA and GATA have been
studied in great detail. Direct assessment of transcription factor
occupancy on silent, liver-specific genes in early mouse embryos
revealed that binding sites for FoxA and GATA transcription
factors, but not sites for various other factors expressed in the liver
lineage, were occupied in the undifferentiated foregut endoderm
(Gualdi et al., 1996). Upon induction of the liver bud, other factors
became engaged with the chromatin to initiate the liver-specific
gene expression program. FoxA and GATA proteins are also
expressed in areas outside the prospective liver region, for example
in the medial-posterior endoderm. Here, their chromatin-binding
activity still endows competence for the induction of liver genes, but
this does not eventuate owing to the restrictive mesodermal
interactions that normally inhibit the liver fate in this tissue
(Bossard and Zaret, 2000; McLin et al., 2007).
Early evidence for the pioneer factor activity of FoxA and GATA
came from attempts to model their binding with purified
components in vitro (Cirillo et al., 1998; Cirillo and Zaret, 1999).
Various liver-specific transcription factors were tested for their
ability to bind to their sites on nucleosomal DNA and to engage
nucleosome arrays harboring their binding sites, where the arrays
were compacted by binding of linker histone. Remarkably, only
purified FoxA protein could engage its target sequence on
nucleosomes and enhance GATA factor binding, whereas the
other factors tested could not. Furthermore, FoxA protein, and to a
lesser extent Gata4, but not other liver-specific factors, could
engage their target sites on the compacted nucleosome arrays and
create a local open domain of chromatin, independent of
nucleosome remodelers. Indeed, this is how the name ‘pioneer
factors’ was coined (Cirillo et al., 2002).
The occupation by FoxA and GATA of a liver-specific enhancer
in endoderm chromatin prior to the specification of liver cells, and
the fact that at least FoxA could target nucleosomal DNA,
suggested that these proteins functioned as competence factors
(Zaret, 1999). Consistent with this, genetic inactivation of FoxA
genes in the endoderm resulted in a failure of the endoderm to
initiate hepatic differentiation (Lee et al., 2005). In C. elegans,
when the FoxA homolog PHA-4 is first expressed it occupies
target sequences of highest affinity, but as its expression is
elevated during endoderm development, PHA-4 begins to occupy
lower affinity targets, indicating that its action in binding to
chromatin is concentration dependent (Gaudet and Mango, 2002).
Recent genomics studies of pancreatic differentiation of human
embryonic stem cells showed that FOXA binding occurs at genes
for various endodermal fates in the endodermal intermediate stage
when competence is acquired (Wang et al., 2015), consistent with
the original hypothesis that pioneer factor binding imparts the
competence to elicit fate changes. Emphasizing the utility of the
mechanism, FoxA and GATA factors appear to be a crucial
component of the network ‘kernel’ that specifies endoderm
competence in all metazoans, over half a billion years of
evolution (Davidson and Erwin, 2006).
Pioneer factors in cell fate conversions
To date, diverse cell fate conversions have been reported by various
combinations of transcription factors, typically including pioneer
factors. The most dramatic example is the reprogramming of
fibroblasts into induced pluripotent stem cells (iPSCs) by only four
Development (2016) 143, 1833-1837 doi:10.1242/dev.133900
transcription factors: Oct3/4, Sox2, Klf4 and c-Myc (Takahashi and
Yamanaka, 2006). Of these factors, Oct3/4, Sox2 and Klf4 act as
pioneer factors in that they can access silent, low signal state
chromatin, regardless of whether they bind together or alone (Soufi
et al., 2012, 2015). By contrast, c-Myc alone prefers to bind to active
chromatin, but can also bind low signal chromatin sites when
cooperating with the other factors (Soufi et al., 2012, 2015). There
are more examples of a combination of cell type-specific pioneer
factors and co-factors directing cell conversion: PU.1 and C/EBPa
can reprogram macrophage-like cells from fibroblasts (Feng et al.,
2008; van Oevelen et al., 2015); Gata4, Mef2c, Tbx5, Hand2 and
Nkx2-5 can reprogram cardiomyocyte-like cells from fibroblasts
(Ieda et al., 2010; Addis et al., 2013); Ascl1, Brn2 (Pou3f2) and
Myt1l can reprogram functional glutaminergic neurons from
fibroblasts (Vierbuchen et al., 2010); and FoxA, Gata4 and
Hnf4α/1α can reprogram hepatocyte-like cells from fibroblasts
(Huang et al., 2011; Sekiya and Suzuki, 2011). In all of these cases,
at least one component of the factor combination plays a central
role as a pioneer factor: PU.1 (macrophage-like cells), Gata4
(cardiomyocyte-like cells), Ascl1 (glutaminergic neurons) and
FoxA (hepatocyte-like cells) (summarized by Iwafuchi-Doi and
Zaret, 2014). For instance, Ascl1 binds silent, low signal chromatin
and recruits Brn2 to target sites, and Brn2 is primarily required for
the later stage of cell conversion by contributing to cell maturation
(Wapinski et al., 2013). These findings demonstrate that even when
the factors are expressed simultaneously, they function in a
hierarchical manner, and that pioneer factors act first to establish a
competence for a specific cell fate, which is followed by co-factor
binding to instruct further differentiation.
Pioneer factors in cancers
As pioneer factors play a primary role in gene regulation, it is no
surprise that their mis-regulation can compromise human health.
Indeed, in many forms of cancer, pioneer factors are up- or
downregulated, mutated or amplified in their genomic region, or
alternatively the DNA sequence of the pioneer factors’ binding
sites is mutated. In esophageal and lung squamous cell
carcinomas, chromosome segments containing SOX2 are often
amplified (Bass et al., 2009). In the case of skin squamous-cell
carcinoma, Sox2 is the most upregulated transcription factor, and
conditional deletion of Sox2 markedly decreases skin tumor
formation (Boumahdi et al., 2014). FoxA and GATA factors are
involved in a variety of hormone-dependent cancers, such as
estrogen receptor (ER)-positive breast cancer, androgen receptor
(AR)-positive prostate cancer, and ER-dependent resistance and
AR-mediated facilitation of liver cancer, and FOXA levels
correlate well with clinical outcomes (reviewed by Jozwik and
Carroll, 2012). Furthermore, single nucleotide polymorphisms at
FOXA binding sites reduce binding of FOXA and ER in liver and
correlate with hepatocellular carcinoma development in female
patients (Li et al., 2012b).
Thus far, non-nuclear receptor transcription factors, such as
pioneer factors, have been considered ‘undruggable’ targets for
cancer treatment, but they could be attractive targets that avoid the
issues of drug resistance that usually occur when targeting
intracellular signaling pathways (Johnston and Carroll, 2015). The
FoxM1-DNA interaction, which is upregulated in a wide range of
cancers, is inhibited by direct interaction with a natural product
called thiostepton (Hegde et al., 2011). Although findings such as
these may hold promise for future cancer treatments, a better
understanding of how pioneer factors function will be required in
order to target them reliably for therapeutic breakthroughs.
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DEVELOPMENT AT A GLANCE
Conclusions
Pioneer factors are among the master regulators of cell fate. They
function by initiating chromatin targeting events on nucleosomal
DNA, typically in low signal chromatin regions where the presence
of linker histones represses transcription. The local exposure of
chromatin brought about by pioneer factor binding allows other,
non-pioneer transcription factors to access nucleosomal DNA,
which in turn drives lineage-specific gene expression and selection
of cell fate. The ability of pioneer factors to target silent genes and
allow other factors to bind provides a mechanistic explanation for
the long-standing phenomenon of developmental competence, in
which a tissue gains the potential to execute a cell fate decision.
However, pioneer factors do not occupy all in silico target sites in
the genome; they are actively excluded from heterochromatic
domains spanned by H3K9me2/3 (type R chromatin) (Lupien et al.,
2008; Soufi et al., 2012), among others. By presenting a barrier to
factor binding, heterochromatic, repressive domains provide a
means for cells to stably retain their fate (Becker et al., 2016). We
suggest that a possible reason for cell conversions being typically of
a low efficiency and failing to shut off their initial genetic program
(Cahan et al., 2014) may relate to the inefficiency of reprogramming
factors in engaging with heterochromatic domains that span genes
for which expression is required for the desired cell type. It is
possible to alter chromatin state broadly by applying small
molecules to target chromatin-modifying enzymes, but such
changes will occur globally throughout the genome. We speculate
that understanding how cell type-specific heterochromatic domains
are established and how pioneer factors can overcome such barriers
during development will provide more targeted ways to manipulate
cell fate in health and disease. More broadly, further work in the
field should be aimed at understanding how different pioneer factors
target silent, low signal-state chromatin and how heterochromatic
features at highly repressed chromatin might block pioneer factor
binding. These detailed mechanistic insights will pave the way for
the future ability to program and reprogram cell fates at will.
Acknowledgements
We thank Eileen Hulme for help in preparing the manuscript.
Competing interests
The authors declare no competing or financial interests.
Funding
Work on pioneer factors was supported by the National Institutes of Health [GM36477
to K.S.Z.] M.I.-D. was supported by postdoctoral fellowships from the Japan Society
for the Promotion of Science and the Naito, Astellas and Uehara foundations.
Development at a Glance
A high-resolution version of the poster is available for downloading in the online
version of this article at http://dev.biologists.org/content/143/11/1833/F1.poster.jpg
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