RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1. (13th October 2017)

• Record Type: Journal Article
• Authors: Xu, Tao; Park, Sung‐Soo; Giaimo, Benedetto Daniele; Hall, Daniel; Ferrante, Francesca; Ho, Diana M; Hori, Kazuya; Anhezini, Lucas; Ertl, Iris; Bartkuhn, Marek; Zhang, Honglai; Milon, Eléna; Ha, Kimberly; Conlon, Kevin P; Kuick, Rork; Govindarajoo, Brandon; Zhang, Yang; Sun, Yuqing; Dou, Yali; Basrur, Venkatesha; Elenitoba‐Johnson, Kojo SJ; Nesvizhskii, Alexey I; Ceron, Julian; Lee, Cheng‐Yu; Borggrefe, Tilman; Kovall, Rhett A; Rual, Jean‐François
• Is Part Of: EMBO journal. Volume 36:Number 21(2017)
• Page Start: 3232
• Page End: 3249
• Publication Date: 2017-10-13
• Subjects: KDM1A -- L3MBTL3 -- Notch signaling -- RBPJ; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201796525
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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 CBF1 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 L3MBTL3 (also known as MBT1) as a novel RBPJ interactor. L3MBTL3 competes with NOTCH ICD for binding to RBPJ. In the absence of NOTCH ICD, RBPJ recruits L3MBTL3 and the histone demethylase KDM1A (also known as LSD1) 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 L3MBTL3 in Drosophila melanogaster and Caenorhabditis elegans demonstrate that the functional link between RBPJ and L3MBTL3 is evolutionarily conserved, thus identifying L3MBTL3 as a universal modulator of Notch signaling in metazoans. Synopsis: The methyl‐lysine reader L3MBTL3 interacts with the Notch co‐activator RBPJ and switches it to a transcriptional repressor via KDM1A demethylase‐mediated removal of activating histone marks at the enhancers of Notch target genes. RBPJ physically and functionally interacts with L3MBTL3. L3MBTL3 competes with NOTCH intracellular domain for binding to RBPJ and for the control of Notch signaling. L3MBTL3 recruits histone demethylase KDM1A to repress Notch target gene expression. Genetic analyses in Drosophila and Caenorhabditis elegans demonstrate that the RBPJ/L3MBTL3 link is evolutionarily conserved in metazoans. Abstract : The methyl‐lysine reader L3MBTL3 switches the Notch coactivator RBPJ to a transcriptional repressor by mediating removal of activating histone marks at Notch target genes.