title: A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters.
abstract: The BCL6 transcriptional repressor is required for the development of germinal center (GC) B cells and diffuse large B cell lymphomas (DLBCLs). Although BCL6 can recruit multiple corepressors, its transcriptional repression mechanism of action in normal and malignant B cells is unknown. We find that in B cells, BCL6 mostly functions through two independent mechanisms that are collectively essential to GC formation and DLBCL, both mediated through its N-terminal BTB domain. These are (1) the formation of a unique ternary BCOR-SMRT complex at promoters, with each corepressor binding to symmetrical sites on BCL6 homodimers linked to specific epigenetic chromatin features, and (2) the "toggling" of active enhancers to a poised but not erased conformation through SMRT-dependent H3K27 deacetylation, which is mediated by HDAC3 and opposed by p300 histone acetyltransferase. Dynamic toggling of enhancers provides a basis for B cells to undergo rapid transcriptional and phenotypic changes in response to signaling or environmental cues.
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Hatzi
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.forename: Chuanxin
authors.initials: C
authors.lastname: Huang
authors.forename: Francine
authors.initials: F
authors.lastname: Garrett-Bakelman
authors.forename: Micah D
authors.initials: MD
authors.lastname: Gearhart
authors.forename: Eugenia G
authors.initials: EG
authors.lastname: Giannopoulou
authors.forename: Paul
authors.initials: P
authors.lastname: Zumbo
authors.forename: Kevin
authors.initials: K
authors.lastname: Kirouac
authors.forename: Srividya
authors.initials: S
authors.lastname: Bhaskara
authors.forename: Jose M
authors.initials: JM
authors.lastname: Polo
authors.forename: Matthias
authors.initials: M
authors.lastname: Kormaksson
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
authors.forename: Fengtian
authors.initials: F
authors.lastname: Xue
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Mason
authors.forename: Scott W
authors.initials: SW
authors.lastname: Hiebert
authors.forename: Gilbert G
authors.initials: GG
authors.lastname: Prive
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.forename: Vivian J
authors.initials: VJ
authors.lastname: Bardwell
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D011401:Promoter Regions, Genetic; D051560:Proto-Oncogene Proteins c-bcl-6; D015398:Signal Transduction
chemical_list: C084103:BCL6 protein, human; C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6
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