Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Consensus DNA motifs recognized by BCL6
The Zn fingers of BCL6 binds to DNA and recognizes specific DNA motifs: the M00424 motif, a consensus sequence for the NKX-homeobox family of transcription factors, the M2 motif, which mimics an M00424 half site; and the M0 motif (see details in Basso et al., 2010).
BCL6 cellular function
- BCL6 cellular function in germinal centers of lymph nodes follicles
Mature naïve B cells migrate from the bone marrow to lymphoid nodes, meet the antigen, they are stimulated to proliferate and further differentiate into centroblasts in germinal centers (GC) of lymphoid follicles. There, cells are subjects to somatic hypermutation and class switch recombination, to further differenciate into memory B cells or plasma cells. This process also requires the presence of follicular helper T cells. BCL6 has a major role in this process. In particular, BCL6 prevents ATM and TP53 (Phan et al., 2004) to induce apoptosis in response to DNA rearrangements such as those necessary for somatic hypermutation and class switch recombination processes. BCL6 is therefore essential for normal B cell development (reviews in Albagli-Curiel, 2003; Jardin et al., 2007; Parekh et al., 2008; Basso and Dalla-Favera, 2010; Pellicano and Holyoake, 2011; Wagner et al., 2011; Basso and Dalla-Favera, 2012; Okada et al., 2012).
- T follicular helper cells
BCL6 is essential for the development of follicular helper T (Tfh) cells. Tfh cells are defined by the expression of the surface markers CXCR5 and PD-1 and synthesis of IL4 and IL21. BCL6 upregulation of B cells in the outer follicle sustains their interactions with helper T cells and allows them to enter the germinal centers (GC) region (Poholek et al., 2010; Kitano et al., 2011; Baumjohann et al., 2011). ICOS induces BCL6, and BCL6 then induces CXCR5. Tfh cells were lost in the absence of B cells, demonstrating a B cell requirement for maintenance of BCL6 and Tfh cell commitment (Choi et al., 2011). BCL6 and MAF cooperate to induce Tfh cell differentiation (Kroenke et al., 2012).
- Other tissues
BCL6 promotes survival of olfactory sensory neurons (Otaki etal., 2010).
BCL6 associate to NACC1 in brain regions (Korutla et al., 2009).
BCL6 forms a complex with BCOR on the promoters of Notch target genes in Xenopus embryos (Sakano et al., 2010).
BCL6-overexpression inhibits osteoclastogenesis, and the PRDM1 (Blimp-1)/BCL6 balance is essential in regulating the bone homeostasis by controlling osteoclastogenesis (Miyauchi et al., 2010).
BCL6 controls the expression of the CC-type chemokine genes and attenuates allergic airway inflammation in pulmonary epithelium (Seto et al. 2011).
BCL6 repression activity
BCL6 binds to DNA as a homodimer and recruits co-repressor molecules, which, in turn, recruit class I and II histone deacetylases. BCL6 and histone deacetylases (HDACs) form stable complexes. BCL6 binds HDACs both directly through its C-terminal Zn fingers and through its N-terminal BTB/POZ domain and indirectly by recruiting several co-repressors such as BCOR, NCOR1, NCOR2 (which bind in a mutually exclusive way to the BTB/POZ domain), CTBP1 (which binds the BTB/POZ and the PEST domains), and MTA3 (which binds the PEST domain). Deacetylation of histones leads to transcriptional repression of BCL6 targets.
BCL6 interacts with ZBTB17 to repress CDKN1A and BCL2 (Phan et al., 2005). BCL6 has also been found to interact with other POK family members ((POZ and Krüppel)/ZBTB (zing finger and BTB) protein family) such as ZBTB7A (LRF) and ZBTB16 (PLZF).
An integrated biochemical and computational approach has recently identified thousands of BCL6 direct target genes, including B cell receptor (BCR; note: nothing to do with BCR, the partner of ABL1) and CD40 signaling genes (involved in signal transduction, MAPK activation, NF-AT activation, and NF-kB activation); T cell-mediated B-cell activation; apoptosis (BCL2, proteins involved in positive and negative regulation of the DISC complex and caspase activation, suggesting a role for BCL6 in balancing pro- and antiapoptotic programs in GC B cells); response to DNA damage (ATM, TP53, CDKN1A, ATR, CHEK1, TP53BP1...); interferon and cytokine signaling (interferon-type and interleukin receptors that lead to activation of JAK/STAT. STAT1, STAT3, and STAT5A were also found to be directly repressed by BCL6); Toll-like receptor signaling; TGFb receptor signaling; and WNT signaling (Basso et al., 2010).
- B cell receptor
B cell receptor (BCR) induces BCL6 phosphorylation by MAPK1 on Ser333 and Ser343, which targets BCL-6 for rapid degradation by the ubiquitin/proteasome pathway (Niu et al., 1998). FBXO11 promotes BCL6 ubiquitylation and degradation (Duan et al., 2012).
- DNA damage
After DNA damage, the kinase ATM promotes BCL6 phosphorylation; follows an interaction with PIN1 required for BCL6 degradation (Phan et al., 2007).
EP300 binds and acetylates BCL6, which inactivates BCL6 (acetylation disrupts the ability of BCL6 to recruit histone deacetylases). The same two pathways (HDAC pathway and SIRT2 pathway) that regulate acetylation-mediated activation of TP53 also control acetylation-mediated inactivation of BCL6 (Bereshchenko et al., 2002). BCL6 represses the expression of EP300 and its cofactor BAT3 (Cerchietti et al., 2010). EP300 acetylates and activates PAX5 (He et al., 2011), which enhances BCL6.
BCL6 protein binds BCL6 gene promoter, and repress BCL6, mechanism of negative autoregulation (Pasqualucci et al., 2003). PATZ1 interacts with BCL6 and is required for its negative autoregulation (Pero et al., 2012).
- CD40 signaling
CD40 signaling activates various pathways, including NF-kB, NF-AT, and AP-1 (Francis et al., 1995). ILF2 (NF45) and ILF3 (NF90) form the nuclear factor of activated T-cells (NF-AT), a crucial transcription factor essential for productive T cell activation (Kao et al., 1994). CD40 signalling reduces BCL6 expression, through induction of IRF4 by the NF-kB pathway (Saito et al., 2007).
- PRDM1 (review in Crotty et al., 2010)
JUND/AP-1 and activated STATs drive high BCL6 expression in GC B cells (Arguni et al., 2006). STAT5 up-regulates BCL6 expression (Scheeren et al., 2005); in contrast, STAT3 up-regulates PRDM1 (Diehl et al., 2008) (the protein coded from PRDM1 is named Blimp-1). BCL6 directly promotes the expression of BACH2, which repress PRDM1 (Blimp-1). BCL6 also suppresses PRDM1 (Blimp-1) through repression of IRF4. IRF4 binds to and induces PRDM1. PRDM1 (Blimp-1) abrogates BCL6. PAX5 (protein name: BSAP) contributes to BCL6 expression (Nera et al., 2006; Tarlinton, 2011). PAX5 abrogates PRDM1 (Blimp-1), which abrogates PAX5. BCL6 and PAX5 promote the expression of AICDA and UNG (which have a major role in somatic hypermutation and class-switch recombination) (Alinikula et al., 2011). BCL6 positively regulates AICDA, IRF8, and MYB via repression of MIR155 (Basso et al., 2012). BCL6 mediates transcriptional repression by recruiting HDACs. MIR155 directly targets HDAC4 and indirectly attenuates BCL6 expression (Sandhu et al., 2012). PRDM1 (Blimp-1) represses BCL6, and also PAX5, MYC, and AICDA (review in Martins and Calame, 2008). IRF8 is expressed at the high levels in germinal center (GC) B cells. IRF8 binds BCL6 promoter and activates BCL6 (Lee et al., 2006).
It is also to be noted that IRF4 is involved in the t(6;14)(p25;q32) IRF4/IGH. PRDM1 (Blimp-1) is inactivated in about 50% of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (ABC- DLBCL) (Mandelbaum et al., 2010).
BCL6 (B-Cell Lymphoma 6)
Atlas Genet Cytogenet Oncol Haematol. 2012-12-01
Online version: http://atlasgeneticsoncology.org/gene/20/bcl6-(b-cell-lymphoma-6)
2007-02-01 BCL6 (B-Cell Lymphoma 6) by Stevan Knezevich
1998-09-01 BCL6 (B-Cell Lymphoma 6) by Jean-Pierre Kerckaert