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BCL6 positively regulates AID and germinal center gene expression via repression of miR-155.

Basso K, Schneider C, Shen Q, Holmes AB, Setty M, Leslie C, Dalla-Favera R - J. Exp. Med. (2012)

Bottom Line: We have identified a core of 15 miRNAs that show binding of BCL6 in their genomic loci and are down-regulated in GC B cells.Similarly, the expression of additional genes relevant for the GC phenotype, including SPI1, IRF8, and MYB, appears to be sustained via BCL6-mediated repression of miR-155.These findings identify a novel mechanism by which BCL6, in addition to repressing protein coding genes, promotes the expression of important GC functions by repressing specific miRNAs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10027, USA. kb451@columbia.edu

ABSTRACT
The BCL6 proto-oncogene encodes a transcriptional repressor that is required for germinal center (GC) formation and whose de-regulation is involved in lymphomagenesis. Although substantial evidence indicates that BCL6 exerts its function by repressing the transcription of hundreds of protein-coding genes, its potential role in regulating gene expression via microRNAs (miRNAs) is not known. We have identified a core of 15 miRNAs that show binding of BCL6 in their genomic loci and are down-regulated in GC B cells. Among BCL6 validated targets, miR-155 and miR-361 directly modulate AID expression, indicating that via repression of these miRNAs, BCL6 up-regulates AID. Similarly, the expression of additional genes relevant for the GC phenotype, including SPI1, IRF8, and MYB, appears to be sustained via BCL6-mediated repression of miR-155. These findings identify a novel mechanism by which BCL6, in addition to repressing protein coding genes, promotes the expression of important GC functions by repressing specific miRNAs.

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Identification of miRNAs that are candidate targets of BCL6 repression in GC B cells. (a) Identification of 15 miRNAs down-regulated in GC B cells, as detected by miRNA expression profiling (miREP), and displaying binding of BCL6 in their promoters (by genome-wide ChIP-on-chip). (b) GSEA was performed on the miRNA targets predicted by both the TargetScan and SVR algorithms. miR-155 and miR-361-5p display a significant enrichment of their targets in genes up-regulated in presence of BCL6 in a B cell line subject to BCL6 silencing and in normal GC compared with non-GC B cells.
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fig1: Identification of miRNAs that are candidate targets of BCL6 repression in GC B cells. (a) Identification of 15 miRNAs down-regulated in GC B cells, as detected by miRNA expression profiling (miREP), and displaying binding of BCL6 in their promoters (by genome-wide ChIP-on-chip). (b) GSEA was performed on the miRNA targets predicted by both the TargetScan and SVR algorithms. miR-155 and miR-361-5p display a significant enrichment of their targets in genes up-regulated in presence of BCL6 in a B cell line subject to BCL6 silencing and in normal GC compared with non-GC B cells.

Mentions: To identify BCL6 target genes in normal GC B cells, we previously used an integrated approach combining genome-wide chromatin immunoprecipitation (ChIP; ChIP-on-chip) analysis to identify promoter regions bound by BCL6, and gene expression profiling to detect protein-coding genes down-regulated in GC (Basso et al., 2010). Here, we undertook a similar approach to identify, in normal GC B cells, candidate BCL6 targets among miRNA genes. Toward this goal, ChIP-on-chip data (Basso et al., 2010) were integrated with miRNA expression profiling (Basso et al., 2009), leading to the identification of 15 miRNA down-regulated in GC B cells compared with naive and/or memory B cells and displaying evidence of BCL6 binding in their regulatory regions (Fig. 1 a).


BCL6 positively regulates AID and germinal center gene expression via repression of miR-155.

Basso K, Schneider C, Shen Q, Holmes AB, Setty M, Leslie C, Dalla-Favera R - J. Exp. Med. (2012)

Identification of miRNAs that are candidate targets of BCL6 repression in GC B cells. (a) Identification of 15 miRNAs down-regulated in GC B cells, as detected by miRNA expression profiling (miREP), and displaying binding of BCL6 in their promoters (by genome-wide ChIP-on-chip). (b) GSEA was performed on the miRNA targets predicted by both the TargetScan and SVR algorithms. miR-155 and miR-361-5p display a significant enrichment of their targets in genes up-regulated in presence of BCL6 in a B cell line subject to BCL6 silencing and in normal GC compared with non-GC B cells.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3526356&req=5

fig1: Identification of miRNAs that are candidate targets of BCL6 repression in GC B cells. (a) Identification of 15 miRNAs down-regulated in GC B cells, as detected by miRNA expression profiling (miREP), and displaying binding of BCL6 in their promoters (by genome-wide ChIP-on-chip). (b) GSEA was performed on the miRNA targets predicted by both the TargetScan and SVR algorithms. miR-155 and miR-361-5p display a significant enrichment of their targets in genes up-regulated in presence of BCL6 in a B cell line subject to BCL6 silencing and in normal GC compared with non-GC B cells.
Mentions: To identify BCL6 target genes in normal GC B cells, we previously used an integrated approach combining genome-wide chromatin immunoprecipitation (ChIP; ChIP-on-chip) analysis to identify promoter regions bound by BCL6, and gene expression profiling to detect protein-coding genes down-regulated in GC (Basso et al., 2010). Here, we undertook a similar approach to identify, in normal GC B cells, candidate BCL6 targets among miRNA genes. Toward this goal, ChIP-on-chip data (Basso et al., 2010) were integrated with miRNA expression profiling (Basso et al., 2009), leading to the identification of 15 miRNA down-regulated in GC B cells compared with naive and/or memory B cells and displaying evidence of BCL6 binding in their regulatory regions (Fig. 1 a).

Bottom Line: We have identified a core of 15 miRNAs that show binding of BCL6 in their genomic loci and are down-regulated in GC B cells.Similarly, the expression of additional genes relevant for the GC phenotype, including SPI1, IRF8, and MYB, appears to be sustained via BCL6-mediated repression of miR-155.These findings identify a novel mechanism by which BCL6, in addition to repressing protein coding genes, promotes the expression of important GC functions by repressing specific miRNAs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10027, USA. kb451@columbia.edu

ABSTRACT
The BCL6 proto-oncogene encodes a transcriptional repressor that is required for germinal center (GC) formation and whose de-regulation is involved in lymphomagenesis. Although substantial evidence indicates that BCL6 exerts its function by repressing the transcription of hundreds of protein-coding genes, its potential role in regulating gene expression via microRNAs (miRNAs) is not known. We have identified a core of 15 miRNAs that show binding of BCL6 in their genomic loci and are down-regulated in GC B cells. Among BCL6 validated targets, miR-155 and miR-361 directly modulate AID expression, indicating that via repression of these miRNAs, BCL6 up-regulates AID. Similarly, the expression of additional genes relevant for the GC phenotype, including SPI1, IRF8, and MYB, appears to be sustained via BCL6-mediated repression of miR-155. These findings identify a novel mechanism by which BCL6, in addition to repressing protein coding genes, promotes the expression of important GC functions by repressing specific miRNAs.

Show MeSH
Related in: MedlinePlus