The zinc-finger protein Zelda is a key activator of the early zygotic genome in Drosophila

Abstract

In all animals, the initial events of embryogenesis are controlled by maternal gene products that are deposited into the developing oocyte. At some point after fertilization, control of embryogenesis is transferred to the zygotic genome in a process called the maternal to zygotic transition (MZT). During this time many maternal RNAs are degraded and transcription of zygotic RNAs ensues1. A longstanding question has been, what factors regulate these events? The recent findings that microRNAs2,3 and Smaugs4 mediate maternal transcript degradation have shed new light on this aspect of the problem. However, the transcription factor(s) that activate the zygotic genome remain elusive. The discovery that many of the early transcribed genes in Drosophila share a cis-regulatory heptamer motif, CAGGTAG and related sequences5,6, collectively referred to as TAGteam sites5 brought up the possibility that a dedicated transcription factor could interact with these sites to activate transcription. Here we report that the zinc-finger protein, Zelda (Zld; Zinc-finger early Drosophila activator), binds specifically to these sites, and is capable of activating transcription in transient transfection assays. Mutant embryos lacking zld are defective in cellular blastoderm formation, and fail to activate many genes essential for cellularization, sex determination, and pattern formation. Global expression profiling confirmed that Zld plays a key role in the activation of the early zygotic genome, and suggests that Zld may also regulate maternal RNA degradation during the MZT.

Pioneer transcription factors in cell reprogramming

“…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).…”

“…Inducing zygotic genome activation Liang et al 2008 Increasing DNA accessibility in native chromatin Harrison et al 2011;Foo et al 2014;Xu et al 2014 Class V Pou (e.g., Oct3/4, Pou5f3) Zygotic genome activation (zebrafish/mouse) Inducing zygotic genome activation Foygel et al 2008;Lee et al 2013 Binding to target sites before zygotic genome activation Leichsenring et al 2013 Reprogramming from fibroblast to iPSCs (mouse/human) Inducing reprogramming Takahashi and Yamanaka 2006 Binding to chromatin that is not DNase-sensitive and not premarked by common histone modifications in vivo Soufi et al 2012 Group B1 Sox (e.g., Sox2) Zygotic genome activation (zebrafish/mouse) Inducing zygotic genome activation Pan and Schultz 2011;Lee et al 2013 Reprogramming from fibroblast to iPSCs (mouse/human) Inducing reprogramming Takahashi and Yamanaka 2006 Binding to chromatin that is nonhypersensitive and not premarked by common histone modifications in vivo Soufi et al 2012 Cancer progression (mouse/human) Inducing tumor formation Bass et al 2009;Boumahdi et al 2014 Klf4…”

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

“…4C): the Tramtrack (TTK) motif (early; 52%), the motif ME38 (early; 38%; ME [for motif-in-enhancers] refers to motifs discovered in Stark et al 2007), and the ME17 motif (late; 58%) were the most frequent ones. Interestingly, Tramtrack is known to repress zygotic expression of fushi tarazu (ftz) prior to the maternal-to-zygotic transition (Pritchard and Schubiger 1996), and ME38 matches the TAGteam motif that is bound by Vielfaltig, an essential activator of zygotic transcription (ten Bosch et al 2006;Liang et al 2008). Both tramtrack and vielfaltig transcripts are maternally deposited to the egg and present at very early stages of Drosophila embryo development.…”

“…Similarly, the early binding sites of other factors are enriched in TAGteam motifs (e.g., early MEF2 binding sites; 1.97-fold; P # 4 3 10 À6 ), suggesting that it is a general determinant of early binding and enhancer function. Interestingly, Vielfaltig is maternally deposited and has been shown to bind to TAGteam motifs, a set of motifs that are enriched in regulatory regions of early blastodermal genes (ten Bosch et al 2006;Liang et al 2008) and in TF binding sites in early D. melanogaster and D. yakuba embryos Bradley et al 2010). Vielfaltig is sufficient to activate enhancers that contain TAGteam motifs and required for early gene expression and cellularization (Liang et al 2008).…”

“…Interestingly, Vielfaltig is maternally deposited and has been shown to bind to TAGteam motifs, a set of motifs that are enriched in regulatory regions of early blastodermal genes (ten Bosch et al 2006;Liang et al 2008) and in TF binding sites in early D. melanogaster and D. yakuba embryos Bradley et al 2010). 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).…”