TitleA hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters.
Publication TypeJournal Article
Year of Publication2013
AuthorsHatzi, Katerina, Jiang Yanwen, Huang ChuanXin, Garrett-Bakelman Francine, Gearhart Micah D., Giannopoulou Eugenia G., Zumbo Paul, Kirouac Kevin, Bhaskara Srividya, Polo Jose M., Kormaksson Matthias, MacKerell Alexander D., Xue Fengtian, Mason Christopher E., Hiebert Scott W., Prive Gilbert G., Cerchietti Leandro, Bardwell Vivian J., Elemento Olivier, and Melnick Ari
JournalCell Rep
Date Published2013 Aug 15
KeywordsAnimals, B-Lymphocytes, Cell Line, Tumor, DNA-Binding Proteins, Heterografts, Humans, Lymphoma, Large B-Cell, Diffuse, Mice, Models, Molecular, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-6, Signal Transduction

<p>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.</p>

Alternate JournalCell Rep
PubMed ID23911289
PubMed Central IDPMC3854650
Grant ListR01 CA071540 / CA / NCI NIH HHS / United States
R01 CA104348 / CA / NCI NIH HHS / United States
R01 CA143032 / CA / NCI NIH HHS / United States
R01 CA164605 / CA / NCI NIH HHS / United States