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Cited by 1,589Genomics and Chromatin DynamicsChromatin Remodeling and CancerEpigenetics and DNA Methylation

Pioneer transcription factors: establishing competence for gene expression

Open access
Zaret, Kenneth S., Carroll, Jason S.·2011·Genes & Development
DOI 10.1101/gad.176826.111PMC PMC3219227
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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.

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Crossref · 10.1101/gad.176826.111

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Claims the paper makes

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  • Premisecitation

    Simple target site affinity was not a predictor of FoxA occupancy, at least in terminally differentiated cells.

    “Simple target site affinity was not a predictor of FoxA occupancy, at least in terminally differentiated cells.”
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    • cites Tuteja et al. 2008

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  • Premisecitation

    All known transcription factors physically occupy less than a few percent of their consensus target sites in the genome.

    “Genome-wide location analyses have shown that all known transcription factors physically occupy less than a few percent of their consensus target sites in the genome (Carr and Biggin 1999;Iyer et al. 2001;Yang et al. 2006;Joseph et al. 2010;Kaplan et al. 2011).”
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    • cites Carr and Biggin 1999

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    • cites Iyer et al. 2001

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    • cites Yang et al. 2006

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  • Interpretationcitation

    Because cells can be genetically reprogrammed without DNA replication, increased accessibility during S-phase chromatin assembly does not generally solve how factors find targets.

    “The ability to genetically reprogram cells in the absence of DNA replication (Chiu and Blau 1984) means that the problem is not generally solved by simply having increased accessibility during chromatin assembly in S phase.”
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    • cites Chiu and Blau 1984

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  • Interpretationreasoning

    The pioneer factor FoxA has passive and active roles in embryonic development, steroid hormone induction, and human cancers.

    “Passive and active roles for the pioneer factor FoxA occur in embryonic development, steroid hormone induction, and human cancers.”
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  • Premisecitation

    In adult mouse liver, FoxA target sites with medium or weak consensus sequences are at genes that are much more liver-specific than genes with strong consensus sequences.

    “On the other hand, careful analysis of genome-wide FoxA binding in the adult mouse liver revealed that FoxA target sites with a medium or weak consensus binding sequence were at genes that are much more liver-specific than genes with a strong consensus sequence (Tuteja et al. 2008).”
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    Interpretationreasoning

    By these criteria, FoxA and GATA are initial and important chromatin-binding factors and were termed pioneer factors.

    “By these criteria, FoxA and GATA are initial and important chromatin-binding factors, and as such were termed pioneer factors.”
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    Premisecitation

    GATA-4 and GATA-6 are redundantly expressed in the foregut endoderm and are necessary for early liver development.

    “GATA-4 and GATA-6 are redundantly expressed in the foregut endoderm and are necessary for early liver development (Holtzinger and Evans 2005;Zhao et al. 2005;Watt et al. 2007).”
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    • cites Holtzinger and Evans 2005

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    • cites Zhao et al. 2005

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    Premisecitation

    FoxA1 and FoxA2 are redundantly expressed in the foregut endoderm and are necessary for liver induction.

    “FoxA1 and FoxA2 are redundantly expressed in the foregut endoderm and are necessary for liver induction (Lee et al. 2005).”
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    • cites Lee et al. 2005

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    Premisecitation

    Many transcription factors individually cannot occupy their target sites on nucleosomal DNA in vitro, but cooperative interactions among a group of such factors can allow nucleosome binding.

    “The importance of cooperative binding is reflected by the observation that many transcription factors individually cannot occupy their target sites on nucleosomal DNA in vitro, but cooperative interactions among a group of such factors can allow nucleosome binding (Adams and Workman 1995;Steger and Workman 1997).”
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    • cites Steger and Workman 1997

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    Interpretationreasoning

    Many or most regulatory regions do not coincide with DNA sequences that assemble into intrinsically unstable nucleosomes, so other mechanisms are needed to expose the DNA.

    “To summarize, many or most regulatory regions do not coincide with DNA sequence that assembles into intrinsically unstable nucleosomes.Thus, other mechanisms are needed to expose the DNA.”
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    Interpretationcitation

    Medium- and lower-affinity liver-specific FoxA targets are highly enriched for binding of other hepatic nuclear factors, suggesting a role for cooperative binding during maintenance of differentiation.

    “Tuteja et al. (2008) did find that medium-and lower-affinity, liver-specific targets were highly enriched for binding of other hepatic nuclear factors, suggesting a role for cooperative binding during the maintenance of differentiation.”
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    • cites Tuteja et al. 2008

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    Interpretationreasoning

    Pioneer factors not only act genetically early in transcription activation but physically bind the genome before activation and before other factors, imparting competence for activity.

    “A distinction about the designation of pioneer factors is that they not only perform a genetic function early in the activation of transcription, but they have been physically shown to bind to the genome for a period prior to activation and prior to other factors binding and, as such, impart competence for activity (Fig. 1).”
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    Interpretationreasoning

    Observations about coregulators, chromatin modifiers, histone modifications, and hypersensitivity do not explain how these become localized to genomic sites initially, so they fail to resolve how regulatory events are initiated at particular locations.

    “However, all of the above observations do not address how general coregulators, chromatin modifiers, histone modifications, and hypersensitivity become localized to genomic sites in the first place and thus fail to resolve the issue of how regulatory events are initiated at particular genomic locations.”
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    Premisecitation

    FoxA and GATA site occupancy preceded occupancy of other enhancer-binding factors in nascent liver and occurred in progenitor cells before gene activation.

    “While the specific dimethyl sulfate protection technique used for in vivo footprinting could have failed to detect other factors, FoxA and GATA site occupancy clearly preceded occupancy of the other enhancer-binding factors in nascent liver and occurred in progenitor cells prior to gene activation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gualdi et al. 1996

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    • Rests on an assumption: The dimethyl sulfate protection technique used for in vivo footprinting did not miss other factors that bound the Alb1 enhancer before FoxA and GATA.

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    Premisecitation

    The two occupied sites in undifferentiated gut endoderm were for FoxA and GATA factors, which are expressed in endoderm and nascent liver and whose binding sites are crucial for Alb1 enhancer function.

    “The binding sites were for FoxA and GATA factors, which are expressed in the endoderm and nascent liver (Ang et al. 1993;Arceci et al. 1993;Monaghan et al. 1993;Laverriere et al. 1994) and whose binding sites are crucial for Alb1 enhancer function (Liu et al. 1991;Bossard and Zaret 1998).”
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    • cites Ang et al. 1993

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    • cites Arceci et al. 1993

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    • cites Liu et al. 1991

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    Premisecitation

    For all transcription factors tested, the vast majority of potential DNA-binding sites are unoccupied, indicating that most nuclear DNA is inaccessible.

    “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.”
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    Premisecitation

    A C-terminal domain of FoxA1, independent of the central DNA-binding domain, binds core histones and is necessary for chromatin opening in vitro.

    “With regard to FoxA1, a C-terminal domain of the protein, independent of the central, DNA-binding domain, binds to core histones and is necessary for chromatin opening in vitro (Cirillo et al. 2002).”
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    Premisecitation

    FoxA1 and FoxA2 together are not necessary for late fetal hepatocyte differentiation but are absolutely essential for embryonic initiation of hepatic differentiation.

    “While the two factors together are also not necessary for late fetal hepatocyte differentiation (Li et al. 2009), they are absolutely essential for the embryonic initiation of hepatic differentiation (Lee et al. 2005).”
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    Premisecitation

    FoxA was more active than GATA in opening compacted chromatin, and FoxE and FoxO can similarly open compacted chromatin.

    “The FoxA factor was more active than the GATA factor in this regard, and studies of FoxE and FoxO have shown that they can similarly open compacted chromatin (Cuesta et al. 2007;Hatta and Cirillo 2007).”
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    Premisecitation

    Chromatin opening properties have also been seen for the basic helix-loop-helix factor TFE3, which in vitro induces hypersensitivity and mediates local nucleosome positioning.

    “Chromatin opening properties have also been seen for the basic helix-loop-helix (bHLH) factor TFE3, which, in vitro, induces hypersensitivity in chromatin and mediates local nucleosome positioning (Ishii et al. 2004).”
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    Premisecitation

    PU.1 and RUNX1 prime transcription of the c-fms/csf1R gene, with RUNX1 needed only transiently.

    “PU.1 and RUNX1 prime transcription of the c-fms/ csf1R gene, with RUNX1 being needed only transiently (Krysinska et al. 2007;Hoogenkamp et al. 2009).”
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    Premisecitation

    Like linker histone, FoxA and other Fox family members are retained on mitotic chromosomes and could serve as bookmarking proteins in mitosis.

    “Also, like linker histone, FoxA and other Fox family members are retained on mitotic chromosomes and thus could serve as ''bookmarking'' proteins in mitosis (Yan et al. 2006;Zaret et al. 2011).”
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    Premisecitation

    FoxA1 and GATA-4, compared with other Alb1 enhancer-binding proteins, were uniquely capable of binding target sites in highly compacted chromatin in vitro and generating local DNase or restriction enzyme sensitivity.

    “For example, direct assessments of FoxA1 and GATA-4, in comparison with other Alb1 enhancer-binding proteins, showed that these pioneer factors were uniquely capable of binding to their target sites in highly compacted chromatin in vitro and generating a local region of DNase or restriction enzyme sensitivity (Cirillo et al. 2002).”
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    • cites Cirillo et al. 2002

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    Interpretationreasoning

    The structure of the FoxA DNA-binding domain appears intermediate between linker histone and other transcription factors, and this feature contributes to pioneer activity.

    “In conclusion, the structure of the FoxA DNA-binding domain appears intermediate between that of linker histone and other transcription factors, and this feature contributes to pioneer activity.”
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    Premisecitation

    From fetal stages onward, FoxA3 is expressed in the liver and apparently provides compensation.

    “Also, from the fetal stages onward, a third homolog, FoxA3, is expressed in the liver and apparently provides compensation ( Z Li et al. 2011).”
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    Interpretationreasoning

    At the Alb1 enhancer, FoxA and GATA sites are bound in endoderm, allowing a rapid and synchronous transcriptional response in cells receiving liver-inductive signals.

    “An example of this is at the aforementioned Alb1 enhancer, where FoxA and GATA factor sites are bound in the endoderm, allowing a rapid and synchronous transcriptional response in the cell population receiving liver-inductive signals.”
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    Premisecitation

    FoxA proteins can bind their target sites on a nucleosome core particle in vitro and in vivo, and the DNA-binding domain alone is sufficient for such binding.

    “Indeed, FoxA proteins can bind their target sites on a nucleosome core particle in vitro and in vivo, and the DNA-binding domain alone is sufficient for such binding (Cirillo et al. 1998;Chaya et al. 2001).”
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    • cites Cirillo et al. 1998

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    • cites Chaya et al. 2001

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    Premisecitation

    FoxA factors lack basic residues on the back side of the globular domain needed for linker-histone-like nucleosome binding; converting analogous residues to basic in FoxA enables tighter nucleosome binding similar to linker histone.

    “While FoxA factors lack the requisite basic residues on the ''back'' side of the globular domain to enable such binding, conversion of analogously positioned residues to basic residues in FoxA enables the factor to bind nucleosomes more tightly, similar to linker histone (Cirillo et al. 1998).”
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    • cites Cirillo et al. 1998

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    Premisecitation

    FoxA proteins move in nuclear chromatin much more slowly than other factors tested, implicating unusually tight chromatin binding in vivo.

    “Notably, FoxA proteins move in nuclear chromatin much more slowly than other factors tested, implicating unusually tight chromatin binding in vivo (Sekiya et al. 2009).”
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    • cites Sekiya et al. 2009

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    Premisecitation

    FoxD3 blocks methylation of an underlying CpG sequence at the silent Alb1 gene in embryonic stem cells, showing that pioneer factor occupancy can modulate the local epigenetic state of chromatin.

    “Notably, FoxD3 was shown to block methylation of an underlying CpG sequence at the silent Alb1 gene in ES cells, demonstrating that pioneer factor occupancy can modulate the local epigenetic state of chromatin (Xu et al. 2009).”
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    Premisecitation

    The rate of FoxA association with nucleosomes is low due to the need for proper rotational phasing of the target site on the nucleosome surface, but the dissociation rate is much lower than for free DNA.

    “The rate of association of FoxA for nucleosomes is low, apparently due to the need for proper rotational phasing of the target site on the nucleosome surface (Sekiya et al. 2009), but the rate of dissociation is much lower than that for free DNA (Cirillo and Zaret 1999).”
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    • cites Cirillo and Zaret 1999

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    Premisecitation

    PU.1 can expand the linker region between nucleosomes and promote local histone modifications, likely enhancing its ability to help other factors bind.

    “PU.1 itself can expand the linker region between nucleosomes and promote local histone modifications, likely contributing to its ability to enhance binding of other factors (Ghisletti et al. 2010;Heinz et al. 2010).”
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    • cites Heinz et al. 2010

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    Premisecitation

    FoxA factors have base-specific contacts with DNA necessary for site-specific binding, whereas linker histone lacks such contacts and does not bind DNA sites specifically.

    “While the FoxA factors have base-specific contacts with DNA that are necessary for site-specific binding (Clark et al. 1993;Sekiya et al. 2009), linker histone lacks such contacts and does not bind DNA sites specifically.”
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    • cites Sekiya et al. 2009

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    Interpretationcitation

    FoxA1 binding can stabilize a nucleosome position, which can phase other local binding sites on and off nucleosomes to modulate factor binding.

    “Thus, binding of FoxA1 can help stabilize a nucleosome position (Shim et al. 1998), which in turn can phase other local binding sites on and off of nucleosomes to modulate factor binding.”
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    Premisecitation

    Grg3 tetramers by themselves avidly bind chromatin but do not elicit closing, defined as conferring resistance to nuclease access.

    “Interestingly, while Grg3 tetramers by themselves avidly bind chromatin, they do not elicit closing, herein defined as conferring resistance to nuclease access (Sekiya and Zaret 2007).”
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    • cites Sekiya and Zaret 2007

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    Premisecitation

    Undifferentiated embryonic endoderm cells express Grg1 and Grg3 when albumin is silent, and both are markedly down-regulated during hepatic specification when albumin is activated.

    “Undifferentiated embryonic endoderm cells express Grg1 and Grg3 when the albumin gene is silent, and both Grgs are markedly down-regulated during hepatic specification when the albumin gene is activated (Santisteban et al. 2010).”
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    Premisecitation

    The yeast Rap1 protein can bind target sites in chromatin and open the domain for other factors.

    “The yeast Rap1 protein can bind target sites in chromatin and open the domain for other factors (Yu and Morse 1999;Koerber et al. 2009).”
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    • cites Koerber et al. 2009

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  • May combine two claims.

    Interpretationreasoning

    Pioneer factors can actively help initiate assembly of regulatory factors by opening chromatin, positioning nucleosomes, enabling cooperative binding, or recruiting chromatin modifiers and coregulators.

    “Pioneer factors can thus actively help initiate the assembly of regulatory factors on the DNA by either opening the chromatin locally, positioning nucleosomes, enabling intrinsic cooperative binding effects among other DNA-binding factors, or directly recruiting other chromatin modifiers and coregulators.”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    FoxA may recruit a corepressor to maintain the silent, competent state, and loss of the corepressor contributes to activation enabled by FoxA and additional factors.

    “Taken together, it appears that FoxA may recruit a corepressor to maintain the silent, competent state, and loss of the corepressor contributes to activation that is enabled by FoxA and additional factors that bind the enhancer during liver induction (Gualdi et al. 1996).”
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    • cites Gualdi et al. 1996

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    Premisecitation

    The yeast Gal4 protein's DNA-binding domain can bind nucleosomal DNA in vitro and in vivo without replication and stabilize distinct nucleosome positions.

    “The yeast Gal4 protein's DNA-binding domain can bind nucleosomal DNA in vitro and in vivo, the latter without replication, and stabilize distinct nucleosome positions (Taylor et al. 1991;Pazin et al. 1998;Balasubramanian and Morse 1999).”
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    • cites Taylor et al. 1991

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    • cites Balasubramanian and Morse 1999

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    Premisecitation

    ER belongs to the nuclear hormone receptor transcription factor family, and some members, including AR and GR, are not stably chromatin-bound in unstimulated cells.

    “ER is a member of the nuclear hormone receptor family of transcription factors, a subset of which, including the androgen receptor (AR) and the GR, is not stably bound to chromatin in unstimulated cells”
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    Interpretationcitation

    FoxA proteins have an N-terminal trans-activation domain that presumably recruits coregulators, which can facilitate other factors entering chromatin.

    “Finally, FoxA proteins have an N-terminal, trans-activation domain (Fig. 3; Pani et al. 1992) that presumably recruits coregulators, which in turn can facilitate other factors to enter the chromatin.”
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    • cites Pani et al. 1992

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    Premisecitation

    FoxA1 binding is needed for ER-induced and ER-repressed genes and for ER binding with estrogen agonist and tamoxifen antagonist.

    “FoxA1 binding is required for genes that are either induced or repressed by ER, as well as for ER binding in the presence of both an agonist (estrogen) and an antagonist (tamoxifen)”
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    • cites Malik et al. 2010

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    • cites Hurtado et al. 2011

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    Interpretationcitation

    Sites where GR induces hypersensitivity are where other factors can subsequently enter chromatin, representing regions where GR serves as a pioneer factor.

    “Although such target sequences may be a minority for GR at the genomic level (John et al. 2011), the sites where GR induces hypersensitivity are where other factors can subsequently enter the chromatin and therefore represent regions where GR serves as a pioneer factor (Voss et al. 2011).”
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    • cites John et al. 2011

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    • cites Voss et al. 2011

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    Interpretationreasoning

    FoxA1 acts as an ER pioneer factor in breast cancer cells, since ER binding depends on it.

    “The dependency of significant ER binding on FoxA1 illustrates that the latter functions as a pioneer factor for ER in breast cancer cells.”
    Quote in the paperSubstantial claim

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    Premisecitation

    ER can positively regulate FoxA1 and GATA3 expression.

    “ER can positively regulate FoxA1 expression (and that of GATA3)”
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    • cites Laganiere et al. 2005

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    Premisecitation

    FoxA1 expression in ER-negative cells causes opportunistic binding to many regions lacking H3K4me1 or H3K4me2, followed by methylation of those residues.

    “expression of FoxA1 in ER-negative cells results in opportunistic binding of FoxA1 to numerous regions lacking H3K4me1 or H3K4me2 marks, followed by subsequent methylation of these histone residues”
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    • cites Serandour et al. 2011

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    Premisecitation

    FoxA1 expression inversely correlates with tumor grade and is linked to better survival.

    “its expression negatively correlates with tumor grade and is associated with better survival”
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    Interpretationcitation

    Defined chromatin features facilitate FoxA1 binding in breast cancer cells: FoxA consensus motif, absence of DNA methylation, nucleosome depletion, and H3K4me1/me2 modification.

    “we conclude that there are defined features of chromatin that can facilitate FoxA1 binding in breast cancer cells”
    Quote in the paperSubstantial claim

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    Premisecitation

    Silencing FoxA1 reduces hypersensitivity at specific ER- and FoxA1-binding regions without changing H3K4me1 or H3K4me2 levels.

    “Specific silencing of FoxA1 decreases the hypersensitivity of specific ER-and FoxA1-binding regions without affecting H3K4me1 or H3K4me2 levels”
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    • cites Lupien et al. 2008

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    Premisecitation

    The human genome contains about one million predicted EREs, over 220,000 of which are optimal binding sequences.

    “;1 million predicted EREs exist in the human genome”
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    • cites Vega et al. 2006

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    • cites Joseph et al. 2010

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    Interpretationcitation

    FoxA1 can enhance and suppress AR binding potential.

    “FoxA1 both positively and negatively regulates AR-binding potential”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    H3K4me1 and H3K4me2 marks are important for FoxA1 binding and consequently for ER binding.

    “implying that the presence of the H3K4me1 and H3K4me2 marks is important for FoxA1 binding (Lupien et al. 2008) and, therefore, ER binding”
    Quote in the paperSubstantial claim

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    Premisecitation

    FoxA1 expression in U20S-ER cells can induce ER binding at regions previously seen only in breast cancer cells and changes estrogen-ER-transcribed genes.

    “Expression of FoxA1 in U20S-ER cells can induce ER binding to regions previously only observed in the breast cancer cells, and this alters the genes that estrogen-ER can transcribe”
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    • cites Hurtado et al. 2011

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    Interpretationreasoning

    FoxA1 acts as a pioneer and regulatory protein for nuclear receptors beyond ER, likely for other hormone-responsive receptors.

    “A role for FoxA1 as a nuclear receptor regulatory protein and pioneer factor is not limited to ER and appears to be a more general phenomenon observed for other hormoneresponsive nuclear receptors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: FoxA1 and FoxA2 interact with the androgen receptor in prostate cancer cells.

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    Premisecitation

    Molecular apocrine breast cancers are ER-negative and AR-positive but have an expression pattern resembling ER-positive breast cancer.

    “Molecular apocrine breast cancers are ER À AR + but express a gene expression pattern resembling an ER + breast cancer”
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    • cites Farmer et al. 2005

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    • cites Doane et al. 2006

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    Interpretationreasoning

    Heavily methylated regions may reduce ER and/or FoxA1 binding potential.

    “heavily methylated regions may negatively impact ERand/or FoxA1-binding potential”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    FoxA1 binding establishes a stable platform for ER cofactor recruitment and chromatin loops with target gene promoters.

    “This establishes a stable platform for recruitment of ER-associated cofactors and mediating chromatin loops with promoters of target genes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    FoxA1 binding further reduces chromatin condensation, which permits ER to access local EREs.

    “Upon FoxA1 binding, chromatin condensation is relieved further, thereby allowing ER to bind to local EREs”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In molecular apocrine breast cancer cells, AR replaces ER and uses FoxA1 to bind regulatory regions normally occupied by ER.

    “In molecular apocrine breast cancer cells, AR substitutes for ER and uses FoxA1 to bind to the regulatory regions normally occupied by ER”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Ni et al. 2011

      Not checked in the free run.

    • cites Robinson et al. 2011

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Pioneer factors accompanying nuclear receptors may be therapeutic targets in hormone-driven solid tumors.

    “it is possible that their accompanying pioneer factors may constitute therapeutic targets”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Nakshatri and Badve 2007

      Not checked in the free run.

    • cites Fu et al. 2011

      Not checked in the free run.

    • cites Hurtado et al. 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GATA proteins can bind condensed chromatin and induce local nuclease hypersensitivity, though more weakly than FoxA1.

    “GATA proteins can bind to condensed chromatin and can induce local nuclease hypersensitivity, albeit more weakly than that by FoxA1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cirillo et al. 2002

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    ER-chromatin interactions involve several pioneer factors that interact and depend on one another.

    “the emerging picture involves multiple pioneer factors that contribute to ER-chromatin interactions, with an interplay and dependency existing between the factors”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In U20S-ER osteosarcoma cells lacking FoxA1 and GATA3, ER binding is redirected to different genomic regions, mediated by GATA4.

    “ER binding is redirected to different regions in the genome (Krum et al. 2008), and this is mediated by GATA4”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Krum et al. 2008

      Not checked in the free run.

    • cites Miranda-Carboni et al. 2011

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    In many gene transduction studies, multiple factors are needed for cellular conversion, and a single ectopic factor converts cells from related germ layer lineages.

    “In many of the gene transduction studies, multiple factors are required for the cellular conversion, and in cases in which a single ectopic factor has been used, it converts cells from related germ layer lineages.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    FoxA factors still bind chromatin sites inaccessible to other factors and enable those factors to bind.

    “FoxA factors still bind chromatin sites when other factors cannot, and enable other factors to bind”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    GATA3 is essential for ER-mediated target gene transcription and for MCF-7 breast cancer cell growth.

    “is essential for ER-mediated transcription of target genes and for growth of MCF-7 breast cancer cells”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Eeckhoute et al. 2007

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Pioneer factors such as FoxA proteins can start these regulatory events partly because they resemble linker histones and have special nucleosome- and chromatin-binding properties.

    “Pioneer factors, including FoxA proteins, can initiate such regulatory events, at least in part due to their resemblance to linker histone, and, hence, special nucleosome-and chromatinbinding properties”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Silencing FoxA1 inhibits proliferation of tamoxifen-resistant MCF-7 cells and tamoxifen-resistant ER-positive breast cancer cells with HER2 amplification.

    “Specific silencing of FoxA1 inhibits the proliferation of tamoxifen-resistant MCF-7 cells”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hurtado et al. 2011

      Not checked in the free run.

    • cites Yamaguchi et al. 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GATA motifs are enriched in AR-binding events in LnCaP prostate cancer cells, and GATA2 is recruited to several AR-binding regions where it is needed for effective AR-chromatin interactions.

    “GATA motifs are also enriched in AR-binding events in LnCaP prostate cancer cells, and GATA2 is shown to be recruited to several AR-binding regions, where it is required for effective AR-chromatin interactions”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wang et al. 2007

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationcitation

    Genes can exist in stable silent yet expression-competent states in stem cells, embryonic progenitors, and differentiated cells.

    “genes can exist in stable states where they are transcriptionally silent, yet competent for expression”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    At many genomic sites, pioneer binding creates local hypersensitivity and promotes recruitment of other transcription factors.

    “there are numerous genomic sites where such ''pioneer'' binding creates local hypersensitivity and promotes the recruitment of other transcription factors”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Voss et al. 2011

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    FoxA binding to nucleosomal target sequences is efficient in vitro with unmodified histones, but in vivo the factor prefers particular modified domains.

    “While FoxA binding to target sequences on nucleosomes is efficient in vitro with unmodified histones, in vivo the factor exhibits preferences for particular modified domains”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    After FoxA1 and GR are recruited to the MMTV promoter, factors such as NF1 and Oct1 can be recruited and increase transcription, sometimes depending on FoxA1.

    “Following FoxA1 and GR recruitment to the MMTV promoter, associated transcription factors, including NF1 and Oct1, can get recruited and increase transcriptional activity, but this can be dependent on the presence of FoxA1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Belikov et al. 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AP-2g binds a significant fraction of ER-binding events and is essential for estrogen-mediated transcription and ER binding.

    “AP-2g binds to a significant fraction of ER-binding events, where it is essential for estrogenmediated transcription and ER binding”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tan et al. 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GATA3 is required for mammary gland development and maintains adult cellular differentiation.

    “GATA3 is required for mammary gland development (Asselin-Labat et al. 2007) and maintains cellular differentiation in the adult”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Asselin-Labat et al. 2007

      Not checked in the free run.

    • cites Kouros-Mehr et al. 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increasing the number of cell divisions during reprogramming lengthens the time for stochastic events and enhances reprogramming efficiency.

    “Increasing the number of cell divisions during reprogramming increases the time for stochastic events to occur, and thus enhances reprogramming efficiency”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hanna et al. 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Only a small subset of targeted cells becomes converted, suggesting either that some cells are competent or that stochastic parameters are involved.

    “Only a small subset of the targeted cells becomes converted, suggesting that either a subset of the cells are competent or stochastic parameters are involved”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yamanaka 2009

      Not checked in the free run.

73 of 73

  • The paper relies on this without support.

    The dimethyl sulfate protection technique used for in vivo footprinting did not miss other factors that bound the Alb1 enhancer before FoxA and GATA.

    “While the specific dimethyl sulfate protection technique used for in vivo footprinting could have failed to detect other factors, FoxA and GATA site occupancy clearly preceded occupancy of the other enhancer-binding factors in nascent liver and occurred in progenitor cells prior to gene activation.”

  • The paper relies on this without support.

    FoxA1 and FoxA2 interact with the androgen receptor in prostate cancer cells.

    “It has been well established that both FoxA1 and FoxA2 interact with the AR, the driving transcription factor in prostate cancer cells.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • By the ability to enter closed chromatin at its own high-affinity sites, and by its functional role in controlling chromatin accessibility at other sites, PU.1 meets the criteria for pioneer factor activity in early pro-T cells.

    “By the ability to enter closed chromatin at its own high-affinity sites, and by its functional role in controlling chromatin accessibility at other sites, PU.1 meets the criteria for “pioneer” factor activity in early pro-T cells (98)”

    From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [98]

    The section “Initiating events in chromatin: pioneer factors bind first” describes PU.1 binding before Pax5 activation in B-cell development and says PU.1 can alter local chromatin. The paper also describes access to compacted chromatin as a pioneer-factor property. It does not establish PU.1 binding at its own high-affinity sites or controlling accessibility at other sites in early pro-T cells; no page numbers were supplied for these passages. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • These reports, together with ours, challenge the concept that NF-κB and other signal-activated TFs are restricted to enhancer regions pre-activated by lineage-determining factors.

    “These reports, together with ours, challenge the concept that NF-κB and other signal-activated TFs are restricted to enhancer regions pre-activated by lineage-determining factors58.”

    From Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading (2017) · cites this paper as [58]

    In “Initiating events in chromatin: pioneer factors bind first” (page unavailable), the review describes PU.1 priming enhancers and facilitating other factors’ binding, including at an enhancer regulated by NF-κB. It does not establish that NF-κB and other signal-activated factors are restricted to pre-activated enhancers; “Interaction between FoxA1 and diverse nuclear receptors” (page unavailable) even describes sites where the signal-responsive glucocorticoid receptor pioneers binding. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Pioneer factors were attributed with special properties that separated them functionally from the rest of TFs.

    “However, these TFs (termed pioneer factors) were attributed with special properties that separated them functionally from the rest of TFs58.”

    From Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading (2017) · cites this paper as [58]

  • FOXA TFs can bind condensed chromatin and act as placeholders or recruit factors for transcriptional initiation.

    “FOXAs have a structural similarity to linker histories and are able to bind condensed chromatin, where they can either passively act as placeholders for recruitment of factors later in development or actively recruit other factors for transcriptional initiation (Sekiya et al., 2009; Zaret and Carroll, 2011).”

    From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Zaret and Carroll, 2011

  • Pioneer factors often must recruit additional non-pioneer sequence-specific transcription factors for efficient enhancer activation.

    “Often, pioneer factors must recruit additional non-pioneer sequence-specific TFs for efficient enhancer activation [30, 31].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [31]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • A 1984 Cell citation has a later volume number than a 2011 citation

    Minor

    The references list Cell volume 258 for a 1984 paper but volume 146 for a 2011 paper. The volume numbers cannot run backward over that interval, so at least one citation is incorrect.

1 of 1

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Authors
Zaret, K. S., & Carroll, J. S.
Affiliations
  • University of Pennsylvania (US)
  • University of Cambridge (GB)
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2011-11-01
Volume
25
Issue
21
Pages
2227-2241
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.176826.111
PMC
PMC3219227
OpenAlex
W2122097157
Semantic Scholar
f9d723b94bcaa230978b0c3de2e657ed1c636702
Cited by
1,589
References
196
Citations by year
2026: 75 · 2025: 68 · 2024: 59 · 2023: 94 · 2022: 114 · 2021: 130 · 2020: 131 · 2019: 121 · 2018: 126 · 2017: 119 · 2016: 141 · 2015: 112 · 2014: 128 · 2013: 107 · 2012: 60
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Cancer Research UK (15602)
  • National Institutes of Health (R37GM36477)
  • National Institute of General Medical Sciences (R37GM36477, R37GM036477)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082623)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
pioneer transcription factors, chromatin accessibility, histone-DNA interactions, chromatin remodeling, FoxA, cooperative binding, gene expression regulation, cellular reprogramming, embryonic development, cancer
MeSH terms
Histones, Humans, Oxidoreductases, N-Demethylating, Protein Binding, Substrate Specificity, Transcription Factors, Gene Expression, Protein Structure, Tertiary

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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