title: Symplekin, a polyadenylation factor, prevents MOZ and MLL activity on HOXA9 in hematopoietic cells.
abstract: MOZ and MLL encoding a histone acetyltransferase and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. We have previously shown that MOZ and MLL cooperate to activate HOXA9 gene expression in hematopoietic stem/progenitors cells. To dissect the mechanism of action of this complex, we decided to identify new proteins interacting with MOZ. We found that the scaffold protein Symplekin that supports the assembly of polyadenylation machinery was identified by mass spectrometry. Symplekin interacts and co-localizes with both MOZ and MLL in immature hematopoietic cells. Its inhibition leads to a decrease of the HOXA9 protein level but not of Hoxa9 mRNA and to an over-recruitment of MOZ and MLL onto the HOXA9 promoter. Altogether, our results highlight the role of Symplekin in transcription repression involving a regulatory network between MOZ, MLL and Symplekin.
authors.affiliation: Inserm U866, Labex LipSTIC team, Faculté de Médecine, Université de Bourgogne, 21000 Dijon, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Largeot
authors.affiliation: Inserm U866, Labex LipSTIC team, Faculté de Médecine, Université de Bourgogne, 21000 Dijon, France; CRP-Santé Laboratoire d'Hémato-Cancérologie Expérimentale, 1526 Luxembourg, Luxembourg.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Paggetti
authors.affiliation: Inserm U866, Labex LipSTIC team, Faculté de Médecine, Université de Bourgogne, 21000 Dijon, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Broséus
authors.affiliation: Inserm U866, Labex LipSTIC team, Faculté de Médecine, Université de Bourgogne, 21000 Dijon, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Aucagne
authors.affiliation: Inserm U866, Labex LipSTIC team, Faculté de Médecine, Université de Bourgogne, 21000 Dijon, France.
authors.forename: Brice
authors.initials: B
authors.lastname: Lagrange
authors.affiliation: Inserm U866, Labex LipSTIC team, Faculté de Médecine, Université de Bourgogne, 21000 Dijon, France.
authors.forename: Romain Z
authors.initials: RZ
authors.lastname: Martin
authors.affiliation: Inserm U866, Labex LipSTIC team, Faculté de Médecine, Université de Bourgogne, 21000 Dijon, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Berthelet
authors.affiliation: Inserm U866, Labex LipSTIC team, Faculté de Médecine, Université de Bourgogne, 21000 Dijon, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Quéré
authors.affiliation: CLIPP (Clinical Innovation Proteomic Platform), 21000 Dijon, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Lucchi
authors.affiliation: CLIPP (Clinical Innovation Proteomic Platform), 21000 Dijon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ducoroy
authors.affiliation: Inserm U866, Labex LipSTIC team, Faculté de Médecine, Université de Bourgogne, 21000 Dijon, France; Hôpital Universitaire, Service d'Hématologie Clinique, 21000 Dijon, France.
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Bastie
authors.affiliation: Inserm U866, Labex LipSTIC team, Faculté de Médecine, Université de Bourgogne, 21000 Dijon, France. Electronic address: Laurent.Delva@u-bourgogne.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Delva
mesh_terms: D002460:Cell Line; D006413:Hematopoietic System / Q000166:cytology*; D051548:Histone Acetyltransferases / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D026723:Polyadenylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D039221:mRNA Cleavage and Polyadenylation Factors / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; C101043:SYMPK protein, human; C097899:homeobox protein HOXA9; D039221:mRNA Cleavage and Polyadenylation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D051548:Histone Acetyltransferases; C108712:KAT6A protein, human
keywords: AMLs; BRPF; C-terminal domain of the RNA-polymerase II; CPSF100; CTD-RNA-PolII; EAF6; Esa1-associated factor 6 ortholog; HAT; HMT; HOX; HOXA9; HSF1; ING5; MLL; MOZ; MOZ/YBF2/SAS2/TIP60 homology domain; MYST; PHD; RUNX1; Spi-1/PU.1; Symplekin; Transcription regulation; acute myeloid leukemias; bromodomain and PHD finger-containing protein; cleavage and polyadenylation specificity factor 100; heat shock factor 1; histone acetyltransferase; histone methyltransferase; homeobox; inhibitor of growth 5; mixed lineage leukemia; monocytic leukemia zinc finger; plant homeodomain; runt-related transcription factor 1; spleen focus forming virus proviral integration oncogene/purine-rich box-1