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An enhancer composed of interlocking submodules controls transcriptional autoregulation of suppressor of hairless.

ABSTRACT: Positive autoregulation is an effective mechanism for the long-term maintenance of a transcription factor's expression. This strategy is widely deployed in cell lineages, where the autoregulatory factor controls the activity of a battery of genes that constitute the differentiation program of a postmitotic cell type. In Drosophila, the Notch pathway transcription factor Suppressor of Hairless activates its own expression, specifically in the socket cell of external sensory organs, via an autoregulatory enhancer called the ASE. Here, we show that the ASE is composed of several enhancer submodules, each of which can independently initiate weak Su(H) autoregulation. Cross-activation by these submodules is critical to ensure that Su(H) rises above a threshold level necessary to activate a maintenance submodule, which then sustains long-term Su(H) autoregulation. Our study reveals the use of interlinked positive-feedback loops to control autoregulation dynamically and provides mechanistic insight into initiation, establishment, and maintenance of the autoregulatory state.

SUBMITTER: Liu F

PROVIDER: S-EPMC4013524 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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An enhancer composed of interlocking submodules controls transcriptional autoregulation of suppressor of hairless.

Liu Feng F Posakony James W JW

Developmental cell 20140401 1

Positive autoregulation is an effective mechanism for the long-term maintenance of a transcription factor's expression. This strategy is widely deployed in cell lineages, where the autoregulatory factor controls the activity of a battery of genes that constitute the differentiation program of a postmitotic cell type. In Drosophila, the Notch pathway transcription factor Suppressor of Hairless activates its own expression, specifically in the socket cell of external sensory organs, via an autoreg ...[more]

PMID: 24735880

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Project description:Throughout the animal kingdom, the Notch signalling pathway allows cells to acquire diversified cell fates. Notch signals are translated into activation of Notch target genes by CSL transcription factors. In the absence of Notch signals, CSL together with co-repressors functions as a transcriptional repressor. In Drosophila, repression of Notch target genes involves the CSL homologue Suppressor of Hairless (Su(H)) and the Notch (N) antagonist Hairless (H) that together form a repressor complex. Guided by crystal structure, three mutations Su(H)LL, Su(H)LLF and Su(H)LLL were generated that specifically affect interactions with the repressor H, and were introduced into the endogenous Su(H) locus by gene engineering. In contrast to the wild type isoform, these Su(H) mutants are incapable of repressor complex formation. Accordingly, Notch signalling activity is dramatically elevated in the homozygotes, resembling complete absence of H activity. It was noted, however, that heterozygotes do not display a dominant H loss of function phenotype. In this work we addressed genetic interactions the three H-binding deficient Su(H) mutants display in combination with H and N null alleles. We included a null mutant of Delta (Dl), encoding the ligand of the Notch receptor, as well as of Su(H) itself in our genetic analyses. H, N or Dl mutations cause dominant wing phenotypes that are sensitive to gene dose of the others. Moreover, H heterozygotes lack bristle organs and develop bristle sockets instead of shafts. The latter phenotype is suppressed by Su(H) null alleles but not by H-binding deficient Su(H) alleles which we attribute to the socket cell specific activity of Su(H). Modification of the dominant wing phenotypes of either H, N or Dl, however, suggested some lack of repressor activity in the Su(H) null allele and likewise in the H-binding deficient Su(H) alleles. Overall, Su(H) mutants are recessive perhaps reflecting self-adjusting availability of Su(H) protein.

Dataset Information

An enhancer composed of interlocking submodules controls transcriptional autoregulation of suppressor of hairless.

Publications

An enhancer composed of interlocking submodules controls transcriptional autoregulation of suppressor of hairless.

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