Foxa2 and H2A.Z Mediate Nucleosome Depletion during Embryonic Stem Cell Differentiation

Li, Zhaoyu; Gadue, Paul; Chen, Kaifu; Jiao, Yang; Tuteja, Geetu; Schug, Jonathan; Li, Wei; Kaestner, Klaus H.

doi:10.1016/j.cell.2012.11.018

Cited by 186 publications

(206 citation statements)

References 33 publications

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“…H2A.Z was initially reported to co-occupy promoters of developmentally important genes with PRC2 component Suz12 in mESCs and repress the expression of these genes [51]. Moreover, H2A.Z was reported to be required for efficient binding of Oct4 to its targets in mESCs [24] and to provide a binding platform for pioneer factor Foxa2 to bind the promoter of genes activated during endoderm differentiation [22,52]. Another histone variant H2A.X was also showed to occupy Cdx2-binding sites on extraembryonic genes and to repress their induction in mESCs and mouse induced pluripotent stem cells [53].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs

et al. 2016

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SOX2 is a key regulator of multiple types of stem cells, especially embryonic stem cells (ESCs) and neural progenitor cells (NPCs).Understanding the mechanism underlying the function of SOX2 is of great importance for realizing the full potential of ESCs and NPCs. Here, through genome-wide comparative studies, we show that SOX2 executes its distinct functions in human ESCs (hESCs) and hESC-derived NPCs (hNPCs) through cell type-and stage-dependent transcription programs. Importantly, SOX2 suppresses non-neural lineages in hESCs and regulates neurogenesis from hNPCs by inhibiting canonical Wnt signaling. In hESCs, SOX2 achieves such inhibition by direct transcriptional regulation of important Wnt signaling modulators, WLS and SFRP2. Moreover, SOX2 ensures pluripotent epigenetic landscapes via interacting with histone variant H2A.Z and recruiting polycomb repressor complex 2 to poise developmental genes in hESCs. Together, our results advance our understanding of the mechanism by which cell type-specific transcription factors control lineage-specific gene expression programs and specify cell fate.

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Section: Discussionmentioning

confidence: 99%

Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs

et al. 2016

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“…Also, DNA hypomethylation is not required for FoxA binding (Serandour et al 2011). In terms of histone variants, FoxA2-binding sites can be preoccupied by H2A.Z during ES cell differentiation to endoderm/hepatic progenitor cells, but these preoccupied sites are only a fraction (16%) of the total FoxA2-binding sites (Li et al 2012a). At this point, the most consistent chromatin feature that predicts engagement of pioneer transcription factors is high intrinsic nucleosome occupancy (Fig.…”

Section: Positive Chromatin Features For Pioneer Factor Bindingmentioning

confidence: 99%

“…Thus, the FoxA and GATA factors act as pioneers for liver specification by engaging chromatin in multipotent progenitors and helping to provide the competence for hepatic fate (Table 1). During ES cell differentiation into endoderm in vitro, some FoxA2-binding sites are preoccupied by H2A.Z, and FoxA2 binding at the sites during endoderm induction results in nucleosome depletion and gene activation (Li et al 2012a). …”

Section: Pioneer Factors In Cell Programming During Developmentmentioning

confidence: 99%

Pioneer transcription factors in cell reprogramming

2014

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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.

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“…The structure of Foxa forkhead box has been solved and resembles that of H1 histone (Clark, Halay, Lai & Burley, 1993). Foxa1 can bind and open compacted chromatin in vitro (Cirillo et al., 2002), while Foxa2 binds nucleosomal DNA in vivo (Li, Schug, Tuteja, White & Kaestner, 2011) and mediates nucleosomal depletion during differentiation (Li et al., 2012). Hence, Foxa proteins have been labeled as “pioneer” factors for their ability to bind highly condensed chromatin first, displacing linker histones, and enable access for subsequent binding of additional transcription factors (Zaret & Carroll, 2011).…”

Section: Introductionmentioning

confidence: 99%

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

et al. 2018

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SummaryIncreasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age‐dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina‐associated domains (LADs) using lamin B1 ChIP‐Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1‐associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24‐deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de‐repression of PPAR‐ and LXR‐dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de‐repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis.

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Foxa2 and H2A.Z Mediate Nucleosome Depletion during Embryonic Stem Cell Differentiation

Cited by 186 publications

References 33 publications

Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs

Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs

Pioneer transcription factors in cell reprogramming

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

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