CAF-1 promotes Notch signaling through epigenetic control of target gene expression during Drosophila development.
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.
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, The Chinese Academy of Sciences, Datun Road 15, Beijing, China.
Zhongsheng
Z
Yu
Honggang
H
Wu
Hanqing
H
Chen
Ruoqi
R
Wang
Xuehong
X
Liang
Jiyong
J
Liu
Changqing
C
Li
Wu-Min
WM
Deng
Renjie
R
Jiao
D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D060227:Imaginal Discs / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D009687:Nuclear Proteins / Q000378:metabolism; D034622:RNA Interference; D051880:Receptors, Notch / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D056505:Retinoblastoma-Binding Protein 4 / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism
C110251:Caf1-55 protein, Drosophila; D017931:DNA Primers; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; C497759:N protein, Drosophila; D009687:Nuclear Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D056505:Retinoblastoma-Binding Protein 4; C088731:Su(H) protein, Drosophila; D014157:Transcription Factors; C066381:ct protein, Drosophila
CAF-1; Drosophila; Epigenetic regulation; H4 acetylation; Notch