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Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands
Published on: January 2, 2018
CAF-1 promotes Notch signaling through epigenetic control of target gene expression during Drosophila development
Zhongsheng Yu1, Honggang Wu, Hanqing Chen
1State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, The Chinese Academy of Sciences, Datun Road 15, Beijing, China.
Abstract:
The histone chaperone CAF-1 is known for its role in DNA replication-coupled histone deposition. However, loss of function causes lethality only in higher multicellular organisms such as mice and flies, but not in unicellular organisms such as yeasts, suggesting that CAF-1 has other important functions than histone deposition during animal development. Emerging evidence indicates that CAF-1 also has a role in higher order chromatin organization and heterochromatin-mediated gene expression; it remains unclear whether CAF-1 has a role in specific signaling cascades to promote gene expression during development. Here, we report that knockdown of one of the subunits of Drosophila CAF-1, dCAF-1-p105 (Caf1-105), results in phenotypes that resemble those of, and are augmented synergistically by, mutations of Notch positive regulatory pathway components. Depletion of dCAF-1-p105 leads to abrogation of cut expression and to downregulation of other Notch target genes in wing imaginal discs. dCAF-1-p105 is associated with Suppressor of Hairless [Su(H)] and regulates its binding to the enhancer region of E(spl)mβ. The association of dCAF-1-p105 with Su(H) on chromatin establishes an active local chromatin status for transcription by maintaining a high level of histone H4 acetylation. In response to induced Notch activation, dCAF-1 associates with the Notch intracellular domain to activate the expression of Notch target genes in cultured S2 cells, manifesting the role of dCAF-1 in Notch signaling. Together, our results reveal a novel epigenetic function of dCAF-1 in promoting Notch pathway activity that regulates normal Drosophila development.
Insights
The histone chaperone CAF-1 (Chromatin Assembly Factor-1) has a novel role in Drosophila development. It promotes Notch signaling by associating with key pathway components, regulating gene expression and chromatin organization.
Area of Science:
- Developmental Biology
- Epigenetics
- Molecular Biology
Background:
- Histone chaperone CAF-1 (Chromatin Assembly Factor-1) is essential for DNA replication-coupled histone deposition.
- CAF-1 loss-of-function is lethal in multicellular organisms, suggesting roles beyond histone deposition during development.
- CAF-1 is implicated in chromatin organization and gene expression, but its role in developmental signaling cascades is unclear.
Purpose of the Study:
- To investigate the function of Drosophila CAF-1 subunit dCAF-1-p105 in developmental signaling.
- To determine if dCAF-1-p105 plays a role in the Notch signaling pathway.
Main Methods:
- Knockdown of dCAF-1-p105 in Drosophila wing imaginal discs.
- Analysis of Notch target gene expression (e.g., cut).
- Chromatin immunoprecipitation to assess protein-DNA interactions (dCAF-1-p105 with Su(H) on E(spl)mβ enhancer).
- Assessment of histone acetylation levels.
- Studies in S2 cells to examine dCAF-1 interaction with Notch intracellular domain upon activation.
Main Results:
- dCAF-1-p105 knockdown phenocopies and synergizes with Notch pathway mutations.
- Depletion of dCAF-1-p105 downregulates Notch target genes, including cut expression.
- dCAF-1-p105 associates with Suppressor of Hairless [Su(H)] and regulates its binding to the E(spl)mβ enhancer.
- dCAF-1-p105 maintains local chromatin activity via histone H4 acetylation.
- dCAF-1 interacts with the Notch intracellular domain to activate target gene expression.
Conclusions:
- dCAF-1-p105 plays a crucial role in Notch pathway activation during Drosophila development.
- This study reveals a novel epigenetic function of dCAF-1 in promoting Notch signaling.
- dCAF-1 contributes to normal development by regulating chromatin status and gene expression in response to developmental cues.
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