A Hybrid Mechanism of Action for BCL6 in B Cells Defined by Formation of Functionally Distinct Complexes at Enhancers and Promoters
Katerina Hatzi,
Yanwen Jiang,
Chuanxin Huang,
Francine Garrett-Bakelman,
Micah D. Gearhart,
Eugenia G. Giannopoulou,
Paul Zumbo,
Kevin Kirouac,
Srividya Bhaskara,
Jose M. Polo,
Matthias Kormaksson,
Alexander D. MacKerell, Jr.,
Fengtian Xue,
Christopher E. Mason,
Scott W. Hiebert,
Gilbert G. Prive,
Leandro Cerchietti,
Vivian J. Bardwell,
Olivier Elemento,
Ari Melnick
Affiliations
Katerina Hatzi
Division of Hematology and Medical Oncology, Weill Cornell Medical College, Cornell University, New York, NY, 10065, USA
Yanwen Jiang
Division of Hematology and Medical Oncology, Weill Cornell Medical College, Cornell University, New York, NY, 10065, USA
Chuanxin Huang
Division of Hematology and Medical Oncology, Weill Cornell Medical College, Cornell University, New York, NY, 10065, USA
Francine Garrett-Bakelman
Division of Hematology and Medical Oncology, Weill Cornell Medical College, Cornell University, New York, NY, 10065, USA
Micah D. Gearhart
Developmental Biology Center, Masonic Cancer Center, and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA
Eugenia G. Giannopoulou
Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA
Paul Zumbo
Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA
Kevin Kirouac
Division of Cancer Genomics and Proteomics, Ontario Cancer Institute, 101 College Street, Toronto, ON M5G 1L7, Canada
Srividya Bhaskara
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA
Jose M. Polo
Australian Regenerative Medicine Institute and Department of Anatomy and Development Biology, Monash University, Victoria 3800, Australia
Matthias Kormaksson
Division of Biostatistics and Epidemiology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA
Alexander D. MacKerell, Jr.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201, USA
Fengtian Xue
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201, USA
Christopher E. Mason
Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA
Scott W. Hiebert
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA
Gilbert G. Prive
Division of Cancer Genomics and Proteomics, Ontario Cancer Institute, 101 College Street, Toronto, ON M5G 1L7, Canada
Leandro Cerchietti
Division of Hematology and Medical Oncology, Weill Cornell Medical College, Cornell University, New York, NY, 10065, USA
Vivian J. Bardwell
Developmental Biology Center, Masonic Cancer Center, and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA
Olivier Elemento
Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA
Ari Melnick
Division of Hematology and Medical Oncology, Weill Cornell Medical College, Cornell University, New York, NY, 10065, USA
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.
