{
 "key": "BCL6",
 "name": "BCL6 / BCL6B",
 "class": "C2H2 zinc finger",
 "aka": [
  "BCL6",
  "BCL6B",
  "BAZF",
  "LAZ3",
  "ZBTB27",
  "ZBTB28",
  "BCL6 binding site",
  "STAT-like GAS element",
  "TTCCTAGAA"
 ],
 "definition": "STAT-like TTCCTAGAA bound by the BTB-ZF repressors BCL6, BCL6B.",
 "consensus": "TTCCTAGAA",
 "dataConsensus": "GCTTTCGAGGAAt",
 "motifCount": 7,
 "bySource": {
  "JASPAR": 2,
  "HOCOMOCO": 2,
  "CIS-BP": 2,
  "Vierstra": 1
 },
 "symbols": [
  "BCL",
  "BCL6",
  "BCL6B"
 ],
 "representative": "BCL6.H14CORE.0.PSM.A",
 "cohesion": 0.8,
 "short": "BCL6 and its paralogue BCL6B (BAZF) are BTB/POZ zinc-finger repressors that bind a nine-base site, TTCCTAGAA, which is a TTCNNNGAA element of the same class that STAT dimers use. That overlap is not incidental: BCL6 represses interleukin-4-induced, STAT6-dependent genes by occupying sites that STAT6 would otherwise use, so the same sequence can be an activating STAT element or a repressed BCL6 element depending on which protein is present. BCL6 is required for germinal center formation and for follicular helper T cells, and its deregulation by chromosomal translocation or promoter mutation occurs in a large fraction of diffuse large B-cell lymphomas. A hit to this motif is ambiguous between BCL6, BCL6B and the STAT family.",
 "long": "## The factors\n\nTwo paralogues: BCL6 (also LAZ3, ZBTB27) and BCL6B (BAZF, ZBTB28). Both have the standard BTB-ZF architecture - an N-terminal BTB/POZ domain, a central region with PEST and RD2 repression motifs, and six C-terminal C2H2 zinc fingers [PMID:8692924]. The BTB domain obligately homodimerizes, and the dimer creates a lateral groove at the interface into which the SMRT and NCOR corepressors dock through a short peptide; the crystal structure of that complex explained how one BTB dimer recruits corepressor and provided the target site for the small-molecule BCL6 inhibitors and degraders developed since [PMID:14690607]. Repression is therefore corepressor-dependent and also involves BCOR and HDAC recruitment. BCL6 is expressed at high levels in germinal center B cells and in follicular helper T cells, at lower levels in macrophages and other tissues [PMID:9171827,19628815]; BCL6B is expressed in endothelium, some T-cell subsets and neural tissue and is much less studied. The two proteins bind DNA as dimers, and the six fingers give a footprint consistent with a nine- to twelve-base site.\n\n## The motif\n\nThe site is written in the literature as TTCCTAGAA, sometimes generalized to TTCCT(A/C)GAA [PMID:7945383,11374866]. Parsed as TTC-CTA-GAA it is a TTCNNNGAA element - structurally the same family of sites that STAT dimers occupy as gamma-interferon activated sequences (GAS elements) [PMID:9110977,11374866]. All the matrices here are consistent with that once strand is taken into account: the HOCOMOCO grade-A BCL6 model reads GCTTTCGAGGAAT and JASPAR MA0463.3 reads GCTTTCGAGGAA, whose reverse complements are TTCCTCGAAAGC, while the BCL6B HT-SELEX models read TGCTTTCTAGGAATTCA, reverse-complementing to TTCCTAGAAAGCA [PMID:23332764]. So BCL6 models favor TTCCTCGAA and BCL6B models TTCCTAGAA; both fit TTCCTNGAA, and the difference at that one central position is the only sequence feature that even hints at a paralogue distinction. It is not enough to act on: the BCL6 and BCL6B models are 0.91-0.97 similar, and the Vierstra archetype for the family is named AC0665:BCL/BCL6B, an explicit statement that the two were not separable. Information content is high for a C2H2 family - the BCL6B matrices reach nearly 30 bits because they include long flanks - but much of that comes from the flanking bases selected in vitro rather than from the core, and long high-information matrices of this kind tend to overfit. One entry in the family contradicts the rest outright: CIS-BP M00227, labelled BCL6, reads TAATTAA and its nearest cross-database neighbors are PRD-like homeodomain motifs. It does not belong with the other BCL6 models.\n\n## Where it acts\n\nBCL6 binds promoters and enhancers of genes that must be held off during the germinal center reaction: DNA damage response and checkpoint genes (TP53, CDKN1A, ATR), differentiation genes (PRDM1), and cytokine and chemokine genes [PMID:21900183,22894929]. In T cells it represses the Th1, Th2 and Th17 programs while promoting the follicular helper program [PMID:19628815]. Because the site is a GAS-type element, BCL6 sites overlap physically with STAT sites at shared loci - the germline immunoglobulin epsilon (Iepsilon) promoter is the worked example, where BCL6 occupancy blocks STAT6-driven transcription and IgE class switching [PMID:10490661]. TTCCTNGAA is AT-rich, CpG-free and about nine informative bases, so chance occurrences are frequent; occupancy is set by BCL6 abundance, which is itself tightly controlled by phosphorylation-triggered degradation and by MYC-driven transcription in the germinal center.\n\n## Biology and disease\n\nBcl6-null mice form no germinal centers, cannot mount high-affinity antibody responses, and develop a lethal inflammatory syndrome with eosinophilia and Th2-skewed cytokine production [PMID:9110977,9171827] - a phenotype that connects directly to the STAT6 antagonism. Bcl6 is also required for follicular helper T cell development, and enforced Bcl6 expression drives T cells into that program [PMID:19628815]. In human disease, BCL6 is the most frequently translocated locus in diffuse large B-cell lymphoma: chromosomal rearrangements juxtapose heterologous promoters to the BCL6 coding sequence and prevent its normal downregulation [PMID:8235596], and point mutations in the BCL6 promoter region have the same effect. BCL6 is also deregulated in follicular lymphoma and in some T-cell lymphomas. The BTB lateral groove has been exploited pharmacologically, with peptide and small-molecule inhibitors and BTB-directed degraders in development [PMID:14690607]. BCL6B has no comparable disease association and is best described as an understudied paralogue.\n\n## Reading a hit\n\nThe central caution is the STAT overlap. A TTCNNNGAA match is compatible with BCL6, with BCL6B, and with STAT1, STAT3, STAT4, STAT5A/B and (with the N4 spacing) STAT6; the sequence does not distinguish a repressed BCL6 site from an activated STAT site, and at some loci the same element is both at different times. If your interest is signaling, do not read a BCL6 motif hit as evidence against STAT involvement, or vice versa - the correct inference is that the locus is contested. Within the family, BCL6 and BCL6B are not separable; the slight preference of BCL6 models for a central C and BCL6B models for a central A is within the noise of a single position. Evidence quality is otherwise good: HOCOMOCO BCL6 and BCL6B core models are grade A with PSM evidence, and JASPAR MA0463.3 and MA0731.1 are HT-SELEX, so direct binding is well supported [PMID:23332764,28473536]. Two practical exclusions: discard CIS-BP M00227 (TAATTAA), which is a homeodomain-like site mislabelled as BCL6, and be wary of scoring with the full 17-position BCL6B matrix, whose extreme information content comes largely from in vitro-selected flanks that are unlikely to be conserved in real promoters. Cell context is the strongest supporting evidence: a germinal center B cell or follicular helper T cell makes a BCL6 call reasonable.",
 "caveats": "The site is a TTCNNNGAA GAS element, so a match is ambiguous between BCL6, BCL6B and the STAT family; BCL6 is documented to repress STAT6-dependent genes by competing for overlapping sites, so a hit indicates a contested element rather than a settled assignment. BCL6 and BCL6B motifs are 0.91-0.97 similar and the Vierstra archetype merges them by name. The nine-base core is AT-rich and CpG-free and occurs often by chance. Two specific data problems: CIS-BP M00227 labelled BCL6 is a homeodomain-like TAATTAA site that does not belong in this family, and the 17-position BCL6B HT-SELEX matrix draws much of its information from selected flanks.",
 "references": [
  {
   "cite": "Ye BH, Lista F, Lo Coco F, et al. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 1993;262:747-50.",
   "pmid": "8235596",
   "url": "https://pubmed.ncbi.nlm.nih.gov/8235596/"
  },
  {
   "cite": "Chang CC, Ye BH, Chaganti RS, et al. BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor. Proc Natl Acad Sci U S A 1996;93:6947-52.",
   "pmid": "8692924",
   "url": "https://pubmed.ncbi.nlm.nih.gov/8692924/"
  },
  {
   "cite": "Dent AL, Shaffer AL, Yu X, et al. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 1997;276:589-92.",
   "pmid": "9110977",
   "url": "https://pubmed.ncbi.nlm.nih.gov/9110977/"
  },
  {
   "cite": "Ye BH, Cattoretti G, Shen Q, et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet 1997;16:161-70.",
   "pmid": "9171827",
   "url": "https://pubmed.ncbi.nlm.nih.gov/9171827/"
  },
  {
   "cite": "Harris MB, Chang CC, Berton MT, et al. Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iepsilon transcription and immunoglobulin E switching. Mol Cell Biol 1999;19:7264-75.",
   "pmid": "10490661",
   "url": "https://pubmed.ncbi.nlm.nih.gov/10490661/"
  },
  {
   "cite": "Ahmad KF, Melnick A, Lax S, et al. Mechanism of SMRT corepressor recruitment by the BCL6 BTB domain. Mol Cell 2003;12:1551-64.",
   "pmid": "14690607",
   "url": "https://pubmed.ncbi.nlm.nih.gov/14690607/"
  },
  {
   "cite": "Nurieva RI, Chung Y, Martinez GJ, et al. Bcl6 mediates the development of T follicular helper cells. Science 2009;325:1001-5.",
   "pmid": "19628815",
   "url": "https://pubmed.ncbi.nlm.nih.gov/19628815/"
  },
  {
   "cite": "Siggs OM, Beutler B. The BTB-ZF transcription factors. Cell Cycle 2012;11:3358-69.",
   "pmid": "22894929",
   "url": "https://pubmed.ncbi.nlm.nih.gov/22894929/"
  },
  {
   "cite": "Beaulieu AM, Sant'Angelo DB. The BTB-ZF family of transcription factors: key regulators of lineage commitment and effector function development in the immune system. J Immunol 2011;187:2841-7.",
   "pmid": "21900183",
   "url": "https://pubmed.ncbi.nlm.nih.gov/21900183/"
  },
  {
   "cite": "Jolma A, Yan J, Whitington T, et al. DNA-binding specificities of human transcription factors. Cell 2013;152:327-39.",
   "pmid": "23332764",
   "url": "https://pubmed.ncbi.nlm.nih.gov/23332764/"
  },
  {
   "cite": "Yin Y, Morgunova E, Jolma A, et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science 2017;356.",
   "pmid": "28473536",
   "url": "https://pubmed.ncbi.nlm.nih.gov/28473536/"
  },
  {
   "cite": "Kawamata N, Miki T, Ohashi K, et al. Recognition DNA sequence of a novel putative transcription factor, BCL6. Biochem Biophys Res Commun 1994;204:366-74.",
   "pmid": "7945383",
   "url": "https://pubmed.ncbi.nlm.nih.gov/7945383/"
  },
  {
   "cite": "Hartatik T, Okada S, Okabe S, et al. Binding of BAZF and Bc16 to STAT6-binding DNA sequences. Biochem Biophys Res Commun 2001;284:26-32.",
   "pmid": "11374866",
   "url": "https://pubmed.ncbi.nlm.nih.gov/11374866/"
  }
 ],
 "timeline": [
  {
   "year": 1993,
   "finding": "BCL-6 was cloned from the chromosome 3q27 translocations of diffuse large-cell lymphoma and found truncated in its 5' noncoding region in a third of cases, identifying a zinc-finger gene whose expression is deregulated in that disease.",
   "methods": "positional cloning of translocation breakpoints, Southern blotting of tumor panels",
   "confidence": "medium",
   "pmids": [
    "8235596"
   ],
   "open": "Whether the protein binds DNA and what it does transcriptionally."
  },
  {
   "year": 1996,
   "finding": "A recombinant BCL6 zinc-finger fusion selected the 14-base site (T/A)NCTTTCNAGG(A/G)AT, and full-length BCL6 was then shown to repress from that site through an autonomous N-terminal repression region including the POZ domain - defining both the word and the activity.",
   "methods": "random-oligonucleotide selection, EMSA, DNase I footprinting, transfection reporters",
   "confidence": "medium",
   "pmids": [
    "7945383",
    "8692924"
   ],
   "open": "Which genes carry the site in vivo."
  },
  {
   "year": 1997,
   "finding": "Two BCL6 knockout lines showed loss of germinal centers with a lethal Th2-skewed inflammatory disease, and the recognition site was noted to resemble STAT binding sequences, with BCL6 able to repress interleukin-4-induced transcription from a STAT6 site - the first statement that this motif is contested between a repressor and a signaling activator.",
   "methods": "mouse gene targeting, immunophenotyping, reporter assays on STAT sites",
   "confidence": "high",
   "pmids": [
    "9110977",
    "9171827"
   ]
  },
  {
   "year": 1999,
   "finding": "BCL6 was shown to bind several STAT6 elements with different affinities and to repress interleukin-4-induced germline epsilon transcription; BCL6-null mice switched to IgE more readily, and the defect disappeared in BCL6-STAT6 double knockouts, making the competition genetically explicit.",
   "methods": "EMSA on STAT6 elements, class-switch assays, double-knockout mice",
   "confidence": "medium",
   "pmids": [
    "10490661"
   ]
  },
  {
   "year": 2001,
   "finding": "The consensus for the paralogue BAZF/BCL6B was determined as ATTCCTAGAAAG, essentially the BCL6 site, and both proteins were shown to bind natural STAT6 elements weakly, with a single C-to-T substitution in the interleukin-4 STAT6 site strongly increasing binding - locating the discrimination between a GAS element and a BCL6 site at one or two bases.",
   "methods": "binding-site selection, EMSA with natural and mutated STAT6 probes",
   "confidence": "medium",
   "pmids": [
    "11374866"
   ]
  },
  {
   "year": 2003,
   "finding": "The crystal structure of the BCL6 BTB homodimer bound to a SMRT peptide showed that two corepressor fragments dock symmetrically into a lateral groove formed at the dimer interface, explaining how dimerization and repression are coupled and giving a druggable surface.",
   "methods": "X-ray crystallography at 2.2 A with biochemical and cellular validation",
   "confidence": "high",
   "pmids": [
    "14690607"
   ]
  },
  {
   "year": 2009,
   "finding": "Bcl6 was shown to be required for follicular helper T cell development and sufficient to drive that program while suppressing other helper lineages, extending the factor's role from the B-cell germinal center to its T-cell partner and in a DNA-binding-dependent manner.",
   "methods": "conditional and retroviral expression in mouse T cells, immunization experiments",
   "confidence": "medium",
   "pmids": [
    "19628815"
   ]
  },
  {
   "year": 2017,
   "finding": "HT-SELEX and methyl-HT-SELEX re-measured both paralogues in vitro and returned the same TTCCTNGAA core with long flanks, which is what the current JASPAR and HOCOMOCO models encode; the in vitro data confirm direct binding but do not separate BCL6 from BCL6B.",
   "methods": "HT-SELEX and methyl-HT-SELEX across human transcription factors",
   "confidence": "high",
   "pmids": [
    "23332764",
    "28473536"
   ]
  }
 ],
 "openQuestions": [
  "Whether BCL6 and the STAT factors actually compete for the same genomic elements, or occupy adjoining but distinguishable subsets, is unsettled: biochemistry shows that one or two bases shift the preference between a GAS element and a BCL6 site, but no genome-wide study has classified occupied TTCNNNGAA elements by which protein binds them in which state.",
  "The only hint of a sequence difference between the paralogues is a central C in BCL6 models against a central A in BCL6B models, and it is unknown whether this is a real preference or a sampling difference between the experiments behind the two matrices.",
  "BCL6B has no disease association and little functional literature, so whether it is a redundant copy of BCL6 in endothelium and T-cell subsets or has its own target set has not been tested.",
  "The CIS-BP entry M00227 labelled BCL6 reads TAATTAA and clusters with PRD-like homeodomain motifs, and nothing explains whether this is a mislabelled model or a record of some indirect association; no BCL6 literature reports binding to an AT-rich homeodomain-type site."
 ],
 "members": [
  {
   "id": "BCL6B (MA0731.1)",
   "source": "JASPAR",
   "consensus": "TGCTTTCTAGGAATTCa",
   "bits": 29.8
  },
  {
   "id": "M02896_2.00",
   "source": "CIS-BP",
   "consensus": "TGCTTTCTAGGAATTCa",
   "bits": 29.8,
   "prov": {
    "inferred": false
   }
  },
  {
   "id": "BCL6.H14CORE.0.PSM.A",
   "source": "HOCOMOCO",
   "consensus": "GCTTTCGAGGAAt",
   "bits": 20.3,
   "prov": {
    "evidence": "PSM",
    "grade": "A"
   }
  },
  {
   "id": "BCL6 (MA0463.3)",
   "source": "JASPAR",
   "consensus": "GCTTTCgAGGAA",
   "bits": 16.1
  },
  {
   "id": "AC0665:BCL/BCL6B:C2H2_ZF",
   "source": "Vierstra",
   "consensus": "GCTTTCtAGGAA",
   "bits": 15.6
  },
  {
   "id": "BCL6B.H14CORE.0.PSM.A",
   "source": "HOCOMOCO",
   "consensus": "CTTTCtAGGAA",
   "bits": 12.2,
   "prov": {
    "evidence": "PSM",
    "grade": "A"
   }
  },
  {
   "id": "M00227_2.00",
   "source": "CIS-BP",
   "consensus": "TAATTAA",
   "bits": 10.4,
   "prov": {
    "inferred": false
   },
   "suspect": true,
   "altFamily": "HD_PRD_LIKE"
  }
 ],
 "url": "https://motif.zhoulab.io/families/bcl6/",
 "generated": "2026-10-21",
 "provenance": "Entry text drafted by a language model reading the primary literature; every cited PMID verified against PubMed. Computed fields derive from JASPAR 2024, HOCOMOCO v14, CIS-BP and the Vierstra archetypes. See https://motif.zhoulab.io/families/methods/"
}