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Cited by 338Genomics and Chromatin DynamicsDevelopmental Biology and Gene RegulationEpigenetics and DNA Methylation

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Zelda Binding in the Early Drosophila melanogaster Embryo Marks Regions Subsequently Activated at the Maternal-to-Zygotic Transition

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Harrison, Melissa M., Li, Xiao-Yong, Kaplan, Tommy, Botchan, Michael R., Eisen, Michael B.·2011·PLoS Genetics
DOI 10.1371/journal.pgen.1002266PMC PMC3197655
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Abstract

The earliest stages of development in most metazoans are driven by maternally deposited proteins and mRNAs, with widespread transcriptional activation of the zygotic genome occurring hours after fertilization, at a period known as the maternal-to-zygotic transition (MZT). In Drosophila, the MZT is preceded by the transcription of a small number of genes that initiate sex determination, patterning, and other early developmental processes; and the zinc-finger protein Zelda (ZLD) plays a key role in their transcriptional activation. To better understand the mechanisms of ZLD activation and the range of its targets, we used chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq) to map regions bound by ZLD before (mitotic cycle 8), during (mitotic cycle 13), and after (late mitotic cycle 14) the MZT. Although only a handful of genes are transcribed prior to mitotic cycle 10, we identified thousands of regions bound by ZLD in cycle 8 embryos, most of which remain bound through mitotic cycle 14. As expected, early ZLD-bound regions include the promoters and enhancers of genes transcribed at this early stage. However, we also observed ZLD bound at cycle 8 to the promoters of roughly a thousand genes whose first transcription does not occur until the MZT and to virtually all of the thousands of known and presumed enhancers bound at cycle 14 by transcription factors that regulate patterned gene activation during the MZT. The association between early ZLD binding and MZT activity is so strong that ZLD binding alone can be used to identify active promoters and regulatory sequences with high specificity and selectivity. This strong early association of ZLD with regions not active until the MZT suggests that ZLD is not only required for the earliest wave of transcription but also plays a major role in activating the genome at the MZT.

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Figures

Figure 1 ZLD binds to TAGteam elements in promoters and regulatory elements prior to zygotic activation. (A) Snapshots of ZLD binding at cycle 8 in the loci containing the early-transcribed genes scute (sc), even-skipped (eve), zerknüllt (zen), CG14014 and CG18269 (B) Enrichment of ZLD binding site variants among ZLD peaks from cycle 8. Peaks were sorted from highest (top) to lowest (bottom) levels of binding and binned into groups of 100. The percent of peaks in each bin containing the appropriate motif within 150 bp of the peak location is indicated by the color of the cell in the left panel, the percent of peaks containing the motif after random repositioning of peaks is shown in the right panel. (C) Sequence motif identified from top 500 ZLD peaks using MEME [14] (D) Distribution of genomic annotations among occurrences of CAGGTAG (top), ZLD peaks at cycle 8 (center), and the expected distribution of annotations (based on their genomic abundance) after randomly repositioning the peaks across the genome (bottom).
Figure 1 ZLD binds to TAGteam elements in promoters and regulatory elements prior to zygotic activation. (A) Snapshots of ZLD binding at cycle 8 in the loci containing the early-transcribed genes scute (sc), even-skipped (eve), zerknüllt (zen), CG14014 and CG18269 (B) Enrichment of ZLD binding site variants among ZLD peaks from cycle 8. Peaks were sorted from highest (top) to lowest (bottom) levels of binding and binned into groups of 100. The percent of peaks in each bin containing the appropriate motif within 150 bp of the peak location is indicated by the color of the cell in the left panel, the percent of peaks containing the motif after random repositioning of peaks is shown in the right panel. (C) Sequence motif identified from top 500 ZLD peaks using MEME [14] (D) Distribution of genomic annotations among occurrences of CAGGTAG (top), ZLD peaks at cycle 8 (center), and the expected distribution of annotations (based on their genomic abundance) after randomly repositioning the peaks across the genome (bottom).CC BY · PubMed Central
Figure 2 Zygotically transcribed ZLD targets are downregulated in embryos depleted for maternal ZLD. (A) Gene expression differences between wildtype embryos and ZLD-depleted embryos [10], among 101 zygotic genes with strong (greater than 500) ZLD cycle 8 binding at promoters (purple), at 270 zygotic genes with weaker ZLD promoter binding (green), and among 1639 zygotic genes with no ZLD promoter binding (orange). Zygotic genes are as defined in [17] (B) Comparison of effect of ZLD depletion and ZLD promoter binding at cycle 8 among maternally deposited genes with no zygotic expression in early embryo (left), genes that are both maternally deposited and zygotically transcribed (center), and genes with exclusively zygotic transcription (right). Classification of genes is as defined in [17].
Figure 2 Zygotically transcribed ZLD targets are downregulated in embryos depleted for maternal ZLD. (A) Gene expression differences between wildtype embryos and ZLD-depleted embryos [10], among 101 zygotic genes with strong (greater than 500) ZLD cycle 8 binding at promoters (purple), at 270 zygotic genes with weaker ZLD promoter binding (green), and among 1639 zygotic genes with no ZLD promoter binding (orange). Zygotic genes are as defined in [17] (B) Comparison of effect of ZLD depletion and ZLD promoter binding at cycle 8 among maternally deposited genes with no zygotic expression in early embryo (left), genes that are both maternally deposited and zygotically transcribed (center), and genes with exclusively zygotic transcription (right). Classification of genes is as defined in [17].CC BY · PubMed Central
Figure 3 At mitotic cycle 8, ZLD marks promoter and non-promoter regions of genes activated at the MZT. The left panel shows the expression patterns of 2,010 genes with exclusively zygotic expression at eight timepoints before and during the MZT (list of zygotically transcribed genes and expression data from [17]). Genes are sorted from early (top) to late (bottom) onset of zygotic transcription. The two panels on the right show the levels of ZLD binding to promoter and non-promoter regions for each gene (grey dots; regions with no detected binding are not plotted). Red lines show average levels of ZLD binding in groups of genes with similar times of transcription onset.
Figure 3 At mitotic cycle 8, ZLD marks promoter and non-promoter regions of genes activated at the MZT. The left panel shows the expression patterns of 2,010 genes with exclusively zygotic expression at eight timepoints before and during the MZT (list of zygotically transcribed genes and expression data from [17]). Genes are sorted from early (top) to late (bottom) onset of zygotic transcription. The two panels on the right show the levels of ZLD binding to promoter and non-promoter regions for each gene (grey dots; regions with no detected binding are not plotted). Red lines show average levels of ZLD binding in groups of genes with similar times of transcription onset.CC BY · PubMed Central
Figure 4 ZLD binding precedes and overlaps transcription-factor binding in regulatory sequences. (A) Fraction of regions highly bound (top 300 regions from [18]) by each of 21 transcription factors involved in anterior-posterior or dorsal-ventral patterning at cycle 14 that are bound by ZLD at cycle 8. As a control, narrow black bars show coverage after random reshuffling of ZLD-bound regions (B) For eight factors from [18], we compare the fraction of genome-wide recognition site occurrences that are occupied by each factor (blue), to the fraction of occupied sites that occur in regions that were bound by ZLD in cycle 8 (green). The significant increase in the probability of a factor binding to its own recognition sites in ZLD-bound regions emphasizes the role that ZLD plays in activation of the zygotic genome. Red bars mark the expected percent of TF-occupied sites among ZLD peaks, even in the absence of a TF-recognition element. We analyzed only the eight factors with clear simple recognition elements based on in vitro binding data.
Figure 4 ZLD binding precedes and overlaps transcription-factor binding in regulatory sequences. (A) Fraction of regions highly bound (top 300 regions from [18]) by each of 21 transcription factors involved in anterior-posterior or dorsal-ventral patterning at cycle 14 that are bound by ZLD at cycle 8. As a control, narrow black bars show coverage after random reshuffling of ZLD-bound regions (B) For eight factors from [18], we compare the fraction of genome-wide recognition site occurrences that are occupied by each factor (blue), to the fraction of occupied sites that occur in regions that were bound by ZLD in cycle 8 (green). The significant increase in the probability of a factor binding to its own recognition sites in ZLD-bound regions emphasizes the role that ZLD plays in activation of the zygotic genome. Red bars mark the expected percent of TF-occupied sites among ZLD peaks, even in the absence of a TF-recognition element. We analyzed only the eight factors with clear simple recognition elements based on in vitro binding data.CC BY · PubMed Central
Figure 5 Early ZLD binding predicts chromatin state at the MZT. (A) Histogram of DNA accessibility based on DNaseI hypersensitivity from [20] among the most strongly bound 1,000 ZLD peaks at cycle 8 (red) and among randomly shuffled peak positions (blue). (B) Comparison of genome-wide ZLD binding at cycle 8 (x-axis) vs. the DNaseI hypersensitivity values at cycle 14 [20], showing a genome-wide correlation coefficient of 0.27 (C) Same as (B), but using ZLD binding from late cycle 14, showing correlation coefficient of 0.43.
Figure 5 Early ZLD binding predicts chromatin state at the MZT. (A) Histogram of DNA accessibility based on DNaseI hypersensitivity from [20] among the most strongly bound 1,000 ZLD peaks at cycle 8 (red) and among randomly shuffled peak positions (blue). (B) Comparison of genome-wide ZLD binding at cycle 8 (x-axis) vs. the DNaseI hypersensitivity values at cycle 14 [20], showing a genome-wide correlation coefficient of 0.27 (C) Same as (B), but using ZLD binding from late cycle 14, showing correlation coefficient of 0.43.CC BY · PubMed Central
Figure 6 ZLD binding dynamics through the MZT. (A) Dynamics of ZLD binding during cycle 8 (top track for each gene), cycle 13 (middle track), and late cycle 14 (bottom track) at three genomic loci: and CG14014/CG18269, HmgZ, and even-skipped (eve) (B) Specificity and sensitivity of the relationship between CAGGTAG and ZLD binding at the three timepoints. Shown are the fractions of the top 1,000 ZLD peaks that contain the motif at the three timepoints (left), and the fraction motif occurrences that are bound by ZLD (right). (C) Distribution of genomic annotations among genomic occurrences of the CAGGTAG motif (blue) and ZLD peaks from three timepoints (green).
Figure 6 ZLD binding dynamics through the MZT. (A) Dynamics of ZLD binding during cycle 8 (top track for each gene), cycle 13 (middle track), and late cycle 14 (bottom track) at three genomic loci: and CG14014/CG18269, HmgZ, and even-skipped (eve) (B) Specificity and sensitivity of the relationship between CAGGTAG and ZLD binding at the three timepoints. Shown are the fractions of the top 1,000 ZLD peaks that contain the motif at the three timepoints (left), and the fraction motif occurrences that are bound by ZLD (right). (C) Distribution of genomic annotations among genomic occurrences of the CAGGTAG motif (blue) and ZLD peaks from three timepoints (green).CC BY · PubMed Central

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Metadata

Authors
Harrison, M. M., Li, X.-Y., Kaplan, T., Botchan, M. R., & Eisen, M. B.
Affiliations
  • University of California, Berkeley (US)
  • QB3 (US)
Corresponding author
Eisen, Michael B.
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2011-10-20
Volume
7
Issue
10
Pages
e1002266
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1002266
PMC
PMC3197655
OpenAlex
W2004533772
Cited by
338
References
41
Citations by year
2026: 14 · 2025: 17 · 2024: 23 · 2023: 23 · 2022: 20 · 2021: 27 · 2020: 23 · 2019: 26 · 2018: 24 · 2017: 31 · 2016: 20 · 2015: 22 · 2014: 20 · 2013: 28 · 2012: 18
FWCI
8.84
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (CA30490)
  • National Human Genome Research Institute (HG002779, R01HG002779)
  • National Cancer Institute (R37 CA3049, R37CA030490)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
Zelda, maternal-to-zygotic transition, Drosophila melanogaster embryo, transcriptional activation, enhancer binding, promoter binding, mitotic cycle, chromatin binding, sex determination
MeSH terms
Animals, Drosophila melanogaster, Female, Mitosis, Nuclear Proteins, Promoter Regions, Genetic, Protein Binding, Transcription Factors, Transcription, Genetic, Zygote, Transcriptional Activation, Genome, Gene Expression Regulation, Developmental, Body Patterning, Sex Determination Processes, Drosophila Proteins, Embryonic Development, Chromatin Immunoprecipitation

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