Temporal Coordination of Gene Networks by Zelda in the Early Drosophila Embryo

Nien, Chung Yi; Liang, Hsiao Lan; Butcher, Stephen; Sun, Yujia; Fu, Shengbo; Gocha, Tenzin; Kirov, Nikolai; Manak, J. Robert; Rushlow, Christine

doi:10.1371/journal.pgen.1002339

Cited by 241 publications

(394 citation statements)

References 61 publications

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“…In the activated CRMs, this CAGGTA motif is extended by guanidine and cytosine at positions 7 and 8, respectively (Fig. 4A); this extended motif overlaps a reported motif for Zelda, a TF required for the activation of gene expression in the early embryo (ten Bosch et al 2006;Liang et al 2008;Harrison et al 2011;Nien et al 2011).…”

Section: Enhancer Architecture Of Snail-bound Crmsmentioning

confidence: 52%

A conserved role for Snail as a potentiator of active transcription

et al. 2014

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The transcription factors of the Snail family are key regulators of epithelial–mesenchymal transitions, cell morphogenesis, and tumor metastasis. Since its discovery in Drosophila ∼25 years ago, Snail has been extensively studied for its role as a transcriptional repressor. Here we demonstrate that Drosophila Snail can positively modulate transcriptional activation. By combining information on in vivo occupancy with expression profiling of hand-selected, staged snail mutant embryos, we identified 106 genes that are potentially directly regulated by Snail during mesoderm development. In addition to the expected Snail-repressed genes, almost 50% of Snail targets showed an unanticipated activation. The majority of “Snail-activated” genes have enhancer elements cobound by Twist and are expressed in the mesoderm at the stages of Snail occupancy. Snail can potentiate Twist-mediated enhancer activation in vitro and is essential for enhancer activity in vivo. Using a machine learning approach, we show that differentially enriched motifs are sufficient to predict Snail's regulatory response. In silico mutagenesis revealed a likely causative motif, which we demonstrate is essential for enhancer activation. Taken together, these data indicate that Snail can potentiate enhancer activation by collaborating with different activators, providing a new mechanism by which Snail regulates development.

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Section: Enhancer Architecture Of Snail-bound Crmsmentioning

confidence: 52%

A conserved role for Snail as a potentiator of active transcription

et al. 2014

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“…Vielfaltig is sufficient to activate enhancers that contain TAGteam motifs and required for early gene expression and cellularization (Liang et al 2008). While this work was under revision, it has further been shown that Vielfaltig binds to ;60% of all genomic instances of the TAGteam motif (Harrison et al 2011;Nien et al 2011). Our demonstration that Vielfaltig is a key determinant of early binding is intriguing and suggests that Vielfaltig might help to open (or keep open) chromatin and allow TFs to access their binding sites on DNA thereby defining early enhancers.…”

Section: Vielfaltig's Tagteam Motif Is a Key Regulator Of Early Tf Bimentioning

confidence: 90%

Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

et al. 2012

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The regulation of gene expression is mediated at the transcriptional level by enhancer regions that are bound by sequence-specific transcription factors (TFs). Recent studies have shown that the in vivo binding sites of single TFs differ between developmental or cellular contexts. How this context-specific binding is encoded in the cis-regulatory DNA sequence has, however, remained unclear. We computationally dissect context-specific TF binding sites in Drosophila, Caenorhabditis elegans, mouse, and human and find distinct combinations of sequence motifs for partner factors, which are predictive and reveal specific motif requirements of individual binding sites. We predict that TF binding in the early Drosophila embryo depends on motifs for the early zygotic TFs Vielfaltig (also known as Zelda) and Tramtrack. We validate experimentally that the activity of Twist-bound enhancers and Twist binding itself depend on Vielfaltig motifs, suggesting that Vielfaltig is more generally important for early transcription. Our finding that the motif content can predict contextspecific binding and that the predictions work across different Drosophila species suggests that characteristic motif combinations are shared between sites, revealing context-specific motif codes (cis-regulatory signatures), which appear to be conserved during evolution. Taken together, this study establishes a novel approach to derive predictive cis-regulatory motif requirements for individual TF binding sites and enhancers. Importantly, the method is generally applicable across different cell types and organisms to elucidate cis-regulatory sequence determinants and the corresponding trans-acting factors from the increasing number of tissue-and cell-type-specific TF binding studies.

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“…The maternal transcription factor Zelda (Zld; zinc finger early Drosophila activator) plays a primary role for the onset of zygotic genome activation in Drosophila embryos (Liang et al 2008;Nien et al 2011). Zld protein is present in nuclei considerably earlier than other key maternal transcription factors such as Bicoid (Bcd) and Dorsal (Dl) proteins and is bound to gene regulatory regions prior to zygotic genome activation (Harrison et al 2011;Nien et al 2011). Zld binding increases DNA accessibility and facilitates the binding of other transcription factors, including Bcd and Dl, to target enhancers (Foo et al 2014;Xu et al 2014 (Foo et al 2014).…”

Section: Pioneer Factors In Zygotic Genome Activationmentioning

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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Temporal Coordination of Gene Networks by Zelda in the Early Drosophila Embryo

Cited by 241 publications

References 61 publications

A conserved role for Snail as a potentiator of active transcription

A conserved role for Snail as a potentiator of active transcription

Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

Pioneer transcription factors in cell reprogramming

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