title: Myogenic differentiation triggers PML nuclear body loss and DAXX relocalization to chromocentres.
abstract: The promyelocytic leukemia protein (PML) is expressed in most normal human tissues and forms nuclear bodies (NBs) that have roles in gene regulation and cellular processes such as DNA repair, cell cycle control, and cell fate decisions. Using murine C2C12 myoblasts, we demonstrate that activation of skeletal muscle differentiation results in loss of PML and PML NBs prior to myotube fusion. Myotube formation was associated with marked chromatin reorganization and the relocalization of DAXX from PML NBs to chromocentres. MyoD expression was sufficient to cause PML NB loss, and silencing of PML induced DAXX relocalization. Fusion of C2C12 cells using the reptilian reovirus p14 fusogenic protein failed to disrupt PML NBs yet still promoted DAXX redistribution and loss; whereas ectopic expression of PML in differentiated cells only partially restored PML NB formation and DAXX localization at NBs. Finally, we determined that the C-terminal SUMO-interacting motif of DAXX is required for its colocalization with ATRX in heterochromatin domains during myotube formation. These data support a model in which activation of myogenic differentiation results in PML NB loss, chromatin reorganization and DAXX relocalization, and provides a paradigm for understanding the consequence of PML loss in other cellular contexts, such as during cancer development and progression.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS, Canada, B3H 4R2.
authors.forename: Jayme
authors.initials: J
authors.lastname: Salsman
authors.affiliation: Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada, M5G 1X8.
authors.forename: Lindsy M
authors.identifier: 0000-0003-0612-5114
authors.initials: LM
authors.lastname: Rapkin
authors.affiliation: Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada, B3H 4R2.
authors.forename: Nandini N
authors.initials: NN
authors.lastname: Margam
authors.affiliation: Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada, B3H 4R2.
authors.forename: Roy
authors.initials: R
authors.lastname: Duncan
authors.affiliation: Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada, M5G 1X8.
authors.forename: David P
authors.initials: DP
authors.lastname: Bazett-Jones
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS, Canada, B3H 4R2.|Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS, Canada, B3H 4R2.
authors.forename: Graham
authors.identifier: 0000-0002-3466-6316
authors.initials: G
authors.lastname: Dellaire
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D056970:Co-Repressor Proteins; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D018832:Molecular Chaperones; D024510:Muscle Development / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C491473:Daxx protein, mouse; D006570:Heterochromatin; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein