A DNA Transcription Code for Cell-Specific Gene Activation by Notch Signaling

Cave, John W.; Loh, Felix; Surpris, Joseph W.; Li, Xia; Caudy, Michael

doi:10.1016/j.cub.2004.12.070

Cited by 86 publications

(134 citation statements)

References 49 publications

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“…Yet, a molecular model for assembly of higher-order complexes has remained elusive. CSL does not dimerize on cognate DNA sites (22,24,25), and previous studies have failed to detect any evidence of cooperativity in the loading of intracellular Notch-derived polypeptides onto CSL/DNA complexes at SPSs (23).…”

mentioning

confidence: 87%

“…To test whether residues engaged in ANK-ANK contacts in the crystal contribute to transcriptional activation of SPS-bearing promoters, we compared the ability of different forms of ICN to induce transcription of a luciferase gene under control of the HES-1 promoter, which has a functionally important SPS element (22,23). In contrast to normal ICN1, mutations that disrupt the predicted dimerization interface either abrogate (R1985A) or diminish (K1946E and E1950K) the ability of ICN1 to induce expression of the HES-1 reporter gene ( Fig.…”

Section: Ank-ank Interactions Drive Dimerization Of Ntcsmentioning

confidence: 99%

“…6]. Both the directionality and the spacing between the paired sites influence Notch-dependent transcription in cellbased assays and transgenic flies, suggesting that the SPS is a specialized response element that modulates or tunes the response of target genes to varying doses of activated Notch (22,23). Accordingly, the promoter of the HES-1 gene, which contains an SPS, responds to lower doses of ICN than does the HES-5 promoter, which lacks an SPS (23).…”

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confidence: 99%

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Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription

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Pear

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Notch receptors control differentiation and contribute to pathologic states such as cancer by interacting directly with a transcription factor called CSL (for CBF-1/Suppressor of Hairless/Lag-1) to induce expression of target genes. A number of Notch-regulated targets, including genes of the hairy/enhancer-of-split family in organisms ranging from Drosophila to humans, are characterized by paired CSL-binding sites in a characteristic head-to-head arrangement. Using a combination of structural and molecular approaches, we establish here that cooperative formation of dimeric Notch transcription complexes on promoters with paired sites is required to activate transcription. Our findings identify a mechanistic step that can account for the exquisite sensitivity of Notch target genes to variation in signal strength and developmental context, enable new strategies for sensitive and reliable identification of Notch target genes, and lay the groundwork for the development of Notch pathway inhibitors that are active on target genes containing paired sites.

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confidence: 87%

Section: Ank-ank Interactions Drive Dimerization Of Ntcsmentioning

confidence: 99%

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confidence: 99%

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Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription

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Sliz

Pear

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

161

218

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“…Importantly, many of the E(spl) genes in Drosophila melanogaster share the same transcription factor binding sites in their promoter regions yet show different patterns of expression during development, suggesting that additional differential coregulators are involved (De Celis et al 1996;Nellesen et al 1999;Wech et al 1999). A subset of the E(spl) genes is regulated by a complex of regulatory proteins bound to a specific module containing binding sites for Suppressor of hairless ½Su(H) and proneural proteins (Nellesen et al 1999;Cave et al 2005).…”

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confidence: 99%

“…Synergistic transcriptional activation by these proteins requires a specific organization of the upstream regulatory regions of the target genes (Cave et al 2005). Since a specifically oriented pair of Su(H) binding sites ½Su(H) paired site, SPS and a bHLH activator binding site (A) are necessary for Notch-proneural synergy it has been proposed that the orientation and/or conformation of Su(H) bound to these sites allows direct interaction with Daughterless, a bHLH activator protein that interacts with Achaete-Scute proneural proteins (Cave et al 2005).…”

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confidence: 99%

Phylogenetic Footprinting Analysis in the Upstream Regulatory Regions of the DrosophilaEnhancer of splitGenes

et al. 2007

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During Drosophila development Suppressor of Hairless ½Su(H)-dependent Notch activation upregulates transcription of the Enhancer of split-Complex ½E(spl)-C genes. Drosophila melanogaster E(spl) genes share common transcription regulators including binding sites for Su(H), proneural, and E(spl) basic-helix-loophelix (bHLH) proteins. However, the expression patterns of E(spl) genes during development suggest that additional factors are involved. To better understand regulators responsible for these expression patterns, recently available sequence and annotation data for multiple Drosophila genomes were used to compare the E(spl) upstream regulatory regions from more than nine Drosophila species. The mg and mb regulatory regions are the most conserved of the bHLH genes. Fine analysis of Su(H) sites showed that high-affinity Su(H) paired sites and the Su(H) paired site plus proneural site (SPS 1 A) architecture are completely conserved in a subset of Drosophila E(spl) genes. The SPS 1 A module is also present in the upstream regulatory regions of the more ancient mosquito and honeybee E(spl) bHLH genes. Additional transcription factor binding sites were identified upstream of the E(spl) genes and compared between species of Drosophila. Conserved sites provide new understandings about E(spl) regulation during development. Conserved novel sequences found upstream of multiple E(spl) genes may play a role in the expression of these genes.

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Trans‐Generational Epigenetic Inheritance

Harper

2010

Handbook of Developmental Science, Behavior, and Genetics

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This chapter addresses the possibility that experientially-induced phenotypic adjustments made by one generation could directly influence the phenotypes of succeeding generations. An overview of what is known about gene regulation and development is presented followed by evidence for trans-generational, epigenetic inheritance in animals, how it might be accomplished, under what conditions, and the implications of these phenomena for our understanding of behavioral development.

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A DNA Transcription Code for Cell-Specific Gene Activation by Notch Signaling

Abstract: The SPS architecture functions to mediate or enable the Notch-proneural transcriptional synergy which drives Notch target gene activation in specific cells. Thus, SPS+A is an architectural DNA transcription code that programs a cell-specific pattern of gene expression.

Cited by 86 publications

References 49 publications

Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription

Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription

Phylogenetic Footprinting Analysis in the Upstream Regulatory Regions of the DrosophilaEnhancer of splitGenes

Trans‐Generational Epigenetic Inheritance

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