Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal center B cells

Katia Basso, Masumichi Saito, Pavel Sumazin, Adam A. Margolin, Kai Wang, Wei Keat Lim, Yukiko Kitagawa, Christof Schneider, Mariano J. Alvarez, Andrea Califano, Riccardo Dalla-Favera

Research output: Contribution to journalArticle

137 Scopus citations

Abstract

BCL6 is a transcriptional repressor required for mature B-cell germinal center (GC) formation and implicated in lymphomagenesis. BCL6's physiologic function is only partially known because the complete set of its targets in GC B cells has not been identified. To address this issue, we used an integrated biochemical-computational-functional approach to identify BCL6 direct targets in normal GC B cells. This approach includes (1) identification of BCL6-bound promoters by genome-wide chromatin immunoprecipitation, (2) inference of transcriptional relationships by the use of a regulatory network reverse engineering approach (ARACNe), and (3) validation of physiologic relevance of the candidate targets down-regulated in GC B cells. Our approach demonstrated that a large set of promoters (> 4000) is physically bound by BCL6 but that only a fraction of them is repressed in GC B cells. This set of 1207 targets identifies several cellular functions directly controlled by BCL6 during GC development, including activation, survival, DNA-damage response, cell cycle arrest, cytokine signaling, Toll-like receptor signaling, and differentiation. These results define a broad role of BCL6 in preventing centroblasts from responding to signals leading to exit from the GC before they complete the phase of proliferative expansion and of antibody affinity maturaton.

Original languageEnglish (US)
Pages (from-to)975-984
Number of pages10
JournalBlood
Volume115
Issue number5
DOIs
StatePublished - Feb 4 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Basso, K., Saito, M., Sumazin, P., Margolin, A. A., Wang, K., Lim, W. K., Kitagawa, Y., Schneider, C., Alvarez, M. J., Califano, A., & Dalla-Favera, R. (2010). Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal center B cells. Blood, 115(5), 975-984. https://doi.org/10.1182/blood-2009-06-227017