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Cited by 30Developmental Biology and Gene RegulationGenomics and Chromatin DynamicsGene Regulatory Network Analysis

A feed-forward relay integrates the regulatory activities of Bicoid and Orthodenticle via sequential binding to suboptimal sites

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Datta, Rhea R., Ling, Jia, Kurland, Jesse, Ren, Xiaotong, Xu, Zhe, Yucel, Gozde, Moore, Jackie, Shokri, Leila +7 more·2018·Genes & Development
DOI 10.1101/gad.311985.118PMC PMC6004077

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Abstract

The K50 (lysine at amino acid position 50) homeodomain (HD) protein Orthodenticle (Otd) is critical for anterior patterning and brain and eye development in most metazoans. In Drosophila melanogaster , another K50HD protein, Bicoid (Bcd), has evolved to replace Otd's ancestral function in embryo patterning. Bcd is distributed as a long-range maternal gradient and activates transcription of a large number of target genes, including otd . Otd and Bcd bind similar DNA sequences in vitro, but how their transcriptional activities are integrated to pattern anterior regions of the embryo is unknown. Here we define three major classes of enhancers that are differentially sensitive to binding and transcriptional activation by Bcd and Otd. Class 1 enhancers are initially activated by Bcd, and activation is transferred to Otd via a feed-forward relay (FFR) that involves sequential binding of the two proteins to the same DNA motif. Class 2 enhancers are activated by Bcd and maintained by an Otd-independent mechanism. Class 3 enhancers are never bound by Bcd, but Otd binds and activates them in a second wave of zygotic transcription. The specific activities of enhancers in each class are mediated by DNA motif variants preferentially bound by Bcd or Otd and the presence or absence of sites for cofactors that interact with these proteins. Our results define specific patterning roles for Bcd and Otd and provide mechanisms for coordinating the precise timing of gene expression patterns during embryonic development.

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  • Flexible enhancer grammar ensures robust gene expression control through suboptimal transcription factor binding motifs, which reinforce the requirement for transcription factor cooperativity and create opportunities for fine-tuning enhancer activity levels.

    “Another means by which flexible enhancer grammar ensures robust gene expression control is through “suboptimal” TF binding motifs, which reinforce the requirement for TF cooperativity and create opportunities for fine-tuning enhancer activity levels [125–128].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [127]

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Cited by

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Authors
Datta, R. R., Ling, J., Kurland, J., Ren, X., Xu, Z., Yucel, G., Moore, J., Shokri, L., Baker, I., Bishop, T., Struffi, P., Levina, R., Bulyk, M. L., Johnston, R. J., & Small, S.
Affiliations
  • New York University (US)
  • Brigham and Women's Hospital (US)
  • Johns Hopkins University (US)
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2018-05-01
Volume
32
Issue
9-10
Pages
723-736
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.311985.118
PMC
PMC6004077
OpenAlex
W2804487653
Cited by
30
References
3
Citations by year
2026: 1 · 2025: 2 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 2
Type
posted content
Language
en
Open access
Licence
cc-by-nc
Locations
  • Genes & Development (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • National Institutes of Health (RO1 HG005287)
  • New York University Dean's Undergraduate Research Fellowship
  • NIH (GM 106090)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords
Bicoid, orthodenticle, enhancer regulation, anterior patterning, Drosophila melanogaster embryo, maternal transcription factors, DNA-binding motifs, cofactors, zygotic transcription, transcriptional activation
MeSH terms
Animals, Drosophila melanogaster, Enhancer Elements, Genetic, Protein Binding, Trans-Activators, Homeodomain Proteins, Gene Expression Regulation, Developmental, Body Patterning, Amino Acid Motifs, Drosophila Proteins, Embryonic Development

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