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

Rhea R. Datta, Jia Ling, Jesse Kurland, Xiaotong Ren, Zhe Xu, Gozde Yucel, Jackie Moore, Leila Shokri, Isabel Baker, Timothy Bishop, Paolo Struffi, Rimma Levina, Martha L. Bulyk, Robert J. Johnston, Stephen Small

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)723-736
Number of pages14
JournalGenes and Development
Volume32
Issue number9-10
DOIs
StatePublished - May 1 2018

Keywords

  • Bicoid
  • Embryo
  • Enhancer
  • Orthodenticle
  • Suboptimal binding
  • Transcription factor binding

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    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. (2018). A feed-forward relay integrates the regulatory activities of bicoid and orthodenticle via sequential binding to suboptimal sites. Genes and Development, 32(9-10), 723-736. https://doi.org/10.1101/gad.311985.118