DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE22884 | GEO | 2010/08/20
SECONDARY ACCESSION(S): PRJNA128141
REPOSITORIES: GEO
Similar Datasets
Project description:Elevated DNA methylation in the first intronic region of the BCL6 locus in B cell lymphomas enforces transcription of the BCL6 gene Promoter tiling arrays were used to investigate the distribution of DNA methylation near the promoter region of BCL6 locus Comparison of DNA methylation at promoter regions of lymphoma (Raji) and myeloma (H929) cell lines by methylated CpG island recovery assay (MIRA-chip)
2010-08-20 | E-GEOD-22884 | biostudies-arrayexpress
Project description:During the humoral immune response mature B-cells undergo a dramatic change in phenotype to enable antibody affinity maturation in germinal centers (GCs). Here, we observe for the first time that these phenotypic changes are accompanied by large-scale reorganization of the genomic architecture that encodes the GCB-cell transcriptional program. The coordinate expression of genes that specify the GCB-cell phenotype – most prominently, BCL6 – is achieved through a non-random, multilayered, chromatin reorganization process involving i) increased promoter connectivity, ii) formation of higher-order enhancer networks, iii) 5’ to 3’ gene looping, and iv) merging of gene neighborhoods that share active epigenetic marks. These cell-specific events are closely linked to binding of GC transcription factors and the structural proteins CTCF and cohesin. The gene encoding the GC master regulator, BCL6, is an anchor point for the formation of GC-specific gene and enhancer loops on chromosome 3. Furthermore, through CRISPR-mediated knockout we demonstrate that a putative locus control region upstream of Bcl6 is required for GCB-cell formation in mice. Thus, architectural reorganization of phenotype-driving gene sets, including assembly of cell type-specific promoter and enhancer networks, may be key to controlling tissue-specific gene expression programs.
2016-09-26 | GSE84022 | GEO
Project description:Aberrant DNA methylation commonly occurs in cancer cells where it has been implicated in the epigenetic silencing of tumor suppressor genes. Additional roles for DNA methylation, such as transcriptional activation, have been predicted but have yet to be clearly demonstrated. The BCL6 oncogene is implicated in the pathogenesis of germinal center-derived B cell lymphomas. We demonstrate that the intragenic CpG islands within the first intron of the human BCL6 locus were hypermethylated in lymphoma cells that expressed high amounts of BCL6 messenger RNA (mRNA). Inhibition of DNA methyltransferases decreased BCL6 mRNA abundance, suggesting a role for these methylated CpGs in positively regulating BCL6 transcription. The enhancer-blocking transcription factor CTCF bound to this intronic region in a methylation-sensitive manner. Depletion of CTCF by short hairpin RNA in neoplastic plasma cells that do not express BCL6 resulted in up-regulation of BCL6 transcription. These data indicate that BCL6 expression is maintained during lymphomagenesis in part through DNA methylation that prevents CTCF-mediated silencing.
| S-EPMC2931164 | biostudies-literature
Project description:Most small-molecule protein degraders act as interface stabilizers ‘molecular glues’ between E3 ubiquitin ligases and target proteins to induce ternary complex formation and ubiquitin-dependent target protein degradation. Here we report polymerization as a novel mechanism for small molecule-induced degradation. Using functional screens in combination with molecular and biochemical assays, we found that BI-3802, which binds to the BTB domain of the oncogenic transcription factor BCL6, induces polymerization of BCL6 into regular helical structures in vitro and foci in vivo. Polymerization precedes degradation by the SIAH1 E3 ubiquitin ligase. Hereby, a VxP amino acid motif on BCL6, distal from the drug-binding BTB domain, is required for SIAH1 binding, ubiquitination and BI-3802-induced degradation. Our findings propose that small molecule-induced polymerization is not only a new modality for targeted protein degradation, but also provides synthetic biology with a tool for tunable protein polymerization and opens new avenues for future drug design.
2020-11-20 | PXD016185 | Pride
Project description:The BCL6 transcriptional repressor is a critical oncogene in diffuse large B-cell lymphomas (DLBCL). The specific BCL6 inhibitor RI-BPI potently kills DLBCL cells. We find that RI-BPI induces a particular gene expression signature in DLBCL. In order to identify classes of drugs that might synergize with RIBPI we examined the connectivity of this signature and found a strong association with HDAC and Hsp90 inhibitors. This was explained by the discovery that BCL6 directly represses the p300 lysine acetyltransferase and its co-factor BAT3. RI-BPI induced expression of p300 and BAT3, and p300 acetyltransferase activity, resulting in acetylation of p300 targets like p53 and Hsp90. As a consequence, RI-BPI could attenuate Hsp90 chaperone function, similar to the effect of Hsp90 and HDAC inhibitors. Induction of p300 and BAT3 was required for the anti-lymphoma effects of RI-BPI since specific blockade of either protein rescued DLBCL cells from the BCL6 inhibitor. RI-BPI synergistically killed DLBCL cells in combination with HDAC inhibitors (SAHA, TSA and VPA) and Hsp90 inhibitors (17-DMAG and PUH71). The combination of RI-BPI and SAHA, or RI-BPI and PU-H71 potently suppressed or even eradicated human DLBCL in mice. BCL6 repression of EP300 thus provides a basis for rational targeted combinatorial therapy for patients with DLBCL. Direct comparison of gene expression levels in DLBCL cell lines after 24hs of treatment with either a Bcl6 inhibitor peptide or control peptide
2010-09-21 | E-GEOD-24236 | biostudies-arrayexpress
Project description:To determine whether BCL6 binds to the certain locus we performed genomic localization studies by chromatin immunoprecipitations (ChIP) using a densely tiled custom oligonucleotide microarray covering the genomic loci of different genes. Keywords: ChIP-chip, Transcription Factor localization The experiment was performed in Ramos cell. Triplicate ChIP with BCL6 or actin (negative control) antibodies were cohybridized to the arrays versus the respective input chromatin.The fold enrichment for each oligonucleotide was calculated as the ratio of Cy5 vs. Cy3. Any peaks involving >5 oligonucleotides and with > 2.5 fold enrichment were considered potentially positive hits.
2010-06-10 | E-GEOD-7673 | biostudies-arrayexpress
Project description:The BCL6 transcriptional repressor is a critical oncogene in diffuse large B-cell lymphomas (DLBCL). The specific BCL6 inhibitor RI-BPI potently kills DLBCL cells. We find that RI-BPI induces a particular gene expression signature in DLBCL. In order to identify classes of drugs that might synergize with RIBPI we examined the connectivity of this signature and found a strong association with HDAC and Hsp90 inhibitors. This was explained by the discovery that BCL6 directly represses the p300 lysine acetyltransferase and its co-factor BAT3. RI-BPI induced expression of p300 and BAT3, and p300 acetyltransferase activity, resulting in acetylation of p300 targets like p53 and Hsp90. As a consequence, RI-BPI could attenuate Hsp90 chaperone function, similar to the effect of Hsp90 and HDAC inhibitors. Induction of p300 and BAT3 was required for the anti-lymphoma effects of RI-BPI since specific blockade of either protein rescued DLBCL cells from the BCL6 inhibitor. RI-BPI synergistically killed DLBCL cells in combination with HDAC inhibitors (SAHA, TSA and VPA) and Hsp90 inhibitors (17-DMAG and PUH71). The combination of RI-BPI and SAHA, or RI-BPI and PU-H71 potently suppressed or even eradicated human DLBCL in mice. BCL6 repression of EP300 thus provides a basis for rational targeted combinatorial therapy for patients with DLBCL.
2010-09-21 | GSE24236 | GEO
Project description:We aimed to identify the response mechanism to EGFR tyrosine kinase inhibition. A431 cells were transfected with mock siRNA or BCL6 siRNA. Cells were then treated with gefitinib. Harvesting was done at 0h, at 24h and at 48h. Two TMT10plex sets were organized as follows: TMT set1: mock 0h (3x, channels 126, 127N and 127C), mock 24h (3x, 128N, 128C and 129N), mock 48h (3x, 129C, 130N, 130C) and internal pooled standard (131) composed from equal aliquots of all samples (mock siRNA and BCL6 siRNA). TMT set2: siBCL6 0h (3x, channels 126, 127N and 127C), siBCL6 24h (3x, 128N, 128C and 129N), siBCL6 48h (3x, 129C, 130N, 130C) and the same internal pooled standard (131) as for set 1.
2020-12-09 | PXD016605 | Pride
Project description:To determine whether BCL6 binds to the certain locus we performed genomic localization studies by chromatin immunoprecipitations (ChIP) using a densely tiled custom oligonucleotide microarray covering the genomic loci of different genes. Keywords: ChIP-chip, Transcription Factor localization
2007-07-07 | GSE7673 | GEO
Project description:Rationale: The BCL6 oncogene is constitutively activated by chromosomal translocations and amplification in ABC-DLBCLs, a class of DLBCLs that respond poorly to current therapies. Yet the role of BCL6 in maintaining these lymphomas has not been investigated. BCL6 mediates its effects by recruiting corepressors to an extended groove motif. Development of effective BCL6 inhibitors requires compounds exceeding the binding affinity of these corepressors. Objectives: To design small molecule inhibitors with superior potency vs. endogenous BCL6 ligands for unmet putative therapeutic needs such as targeting ABC-DLBCL. Findings: We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor with 10-fold greater potency than endogenous corepressors. The compound, called FX1, binds in such a way as to occupy an essential region of the BCL6 lateral groove. FX1 disrupts BCL6 repression complex formation, reactivates BCL6 target genes, and mimics the phenotype of mice engineered to express BCL6 with lateral groove mutations. This compound eradicated established DLBCLs xenografts at low doses. Most strikingly, FX1 suppressed ABC-DLBCL cells as well as primary human ABC-DLBCL specimens ex vivo. Conclusions: ABC-DLBCL is a BCL6 dependent disease that can be targeted by novel inhibitors able to exceed the binding affinity of natural BCL6 ligands.
2016-10-12 | GSE80351 | GEO