title: NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function.
abstract: Activating mutations in NOTCH1, an essential regulator of T cell development, are frequently found in human T cell acute lymphoblastic leukemia (T-ALL). Despite important advances in our understanding of Notch signal transduction, the regulation of Notch functions in the nucleus remains unclear. Using immunoaffinity purification, we identified NOTCH1 nuclear partners in T-ALL cells and showed that, beyond the well-characterized core activation complex (ICN1-CSL-MAML1), NOTCH1 assembles a multifunctional complex containing the transcription coactivator AF4p12, the PBAF nucleosome remodeling complex, and the histone demethylases LSD1 and PHF8 acting through their demethylase activity to promote epigenetic modifications at Notch-target genes. Remarkably, LSD1 functions as a corepressor when associated with CSL-repressor complex and as a NOTCH1 coactivator upon Notch activation. Our work provides new insights into the molecular mechanisms that govern Notch transcriptional activity and represents glimpse into NOTCH1 interaction landscape, which will help in deciphering mechanisms of NOTCH1 functions and regulation.
authors.affiliation: INSERM U955, Créteil, France. ahmad.yatim@inserm.fr
authors.forename: Ahmad
authors.initials: A
authors.lastname: Yatim
authors.forename: Clarisse
authors.initials: C
authors.lastname: Benne
authors.forename: Bijan
authors.initials: B
authors.lastname: Sobhian
authors.forename: Sabine
authors.initials: S
authors.lastname: Laurent-Chabalier
authors.forename: Olivier
authors.initials: O
authors.lastname: Deas
authors.forename: Jean-Gabriel
authors.initials: JG
authors.lastname: Judde
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Lelievre
authors.forename: Yves
authors.initials: Y
authors.lastname: Levy
authors.forename: Monsef
authors.initials: M
authors.lastname: Benkirane
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006367:HeLa Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D016513:Mice, SCID; D008957:Models, Genetic; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous
chemical_list: D004268:DNA-Binding Proteins; C430872:MAML1 protein, human; D015513:Oncogene Proteins; D051881:Receptor, Notch1; D014157:Transcription Factors; D056466:Histone Demethylases; C511934:PHF8 protein, human; C495195:KDM1A protein, human