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Notch signaling is an evolutionarily conserved signal transduction pathway that is essential for metazoan development. Upon ligand binding, the Notch intracellular domain ( NOTCH ICD ) translocates into the nucleus and forms a complex with the transcription factor  RBPJ  (also known as  CBF 1 or  CSL ) to activate expression of Notch target genes. In the absence of a Notch signal,  RBPJ  acts as a transcriptional repressor. Using a proteomic approach, we identified L3 MBTL 3 (also known as  MBT 1) as a novel  RBPJ  interactor. L3 MBTL 3 competes with  NOTCH ICD  for binding to  RBPJ . In the absence of  NOTCH ICD ,  RBPJ  recruits L3 MBTL 3 and the histone demethylase  KDM 1A (also known as  LSD 1) to the enhancers of Notch target genes, leading to H3K4me2 demethylation and to transcriptional repression. Importantly,  in vivo  analyses of the homologs of   RBPJ   and  L3 MBTL 3  in  Drosophila melanogaster  and  Caenorhabditis elegans  demonstrate that the functional link between   RBPJ   and  L3 MBTL 3  is evolutionarily conserved, thus identifying L3 MBTL 3 as a universal modulator of Notch signaling in metazoans.

RBPJ / CBF 1 interacts with L3 MBTL 3/ MBT 1 to promote repression of Notch signaling via histone demethylase KDM 1A/ LSD 1