Transcriptomics

Dataset Information

6

Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response


ABSTRACT: Physiologically, Notch signal transduction plays a pivotal role in differentiation; pathologically, Notch signaling contributes to the development of cancer. Transcriptional activation of Notch target genes involves cleavage of the Notch receptor in response to ligand binding, production of the Notch intracellular domain (NICD), and NICD migration into the nucleus and assembly of a coactivator complex. Posttranslational modifications of the NICD are important for its transcriptional activity and protein turnover. Deregulation of Notch signaling and stabilizing mutations of Notch1 have been linked to leukemia development. We found that the methyltransferase CARM1 (coactivator-associated arginine methyltransferase 1; also known as PRMT4) methylated NICD at five conserved arginine residues within the C-terminal transactivation domain. CARM1 physically and functionally interacted with the NICD-coactivator complex and was found at gene enhancers in a Notch-dependent manner. Although a methylation-defective NICD mutant was biochemically more stable, this mutant was biologically less active as measured with Notch assays in embryos of Xenopus laevis and Danio rerio. Mathematical modeling indicated that full but short and transient Notch signaling required methylation of NICD. Analysis of gene expression upon inactivation and activation of Notch signaling in Beko cells. Beko cells were treated with DAPT or DMSO for 24h. Or Beko cells were infected with a DNMAML-ER or Notch1-ER fusion protein. After Selection cells were treated with 4-OHT (Tamoxifen) or Ethanol for 48h.

ORGANISM(S): Mus musculus  

SUBMITTER: Tilman Borggrefe   Jan E Sträng  Robert Liefke  Michael Kühl  Wiebke Cizelsky  Francesca Ferrante  Ina M Berger  Gerhard Mittler  Franz Oswald  Kerstin Hein  Hans A Kestler  Steffen Just 

PROVIDER: E-GEOD-62528 | ArrayExpress | 2015-03-26

SECONDARY ACCESSION(S): GSE62528PRJNA264337

REPOSITORIES: GEO, ArrayExpress

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Publications

Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response.

Hein Kerstin K   Mittler Gerhard G   Cizelsky Wiebke W   Kühl Michael M   Ferrante Francesca F   Liefke Robert R   Berger Ina M IM   Just Steffen S   Sträng J Eric JE   Kestler Hans A HA   Oswald Franz F   Borggrefe Tilman T  

Science signaling 20150324 369


Physiologically, Notch signal transduction plays a pivotal role in differentiation; pathologically, Notch signaling contributes to the development of cancer. Transcriptional activation of Notch target genes involves cleavage of the Notch receptor in response to ligand binding, production of the Notch intracellular domain (NICD), and NICD migration into the nucleus and assembly of a coactivator complex. Posttranslational modifications of the NICD are important for its transcriptional activity and  ...[more]

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