title: BCL6 positively regulates AID and germinal center gene expression via repression of miR-155.
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.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10027, USA. kb451@columbia.edu
authors.forename: Katia
authors.initials: K
authors.lastname: Basso
authors.forename: Christof
authors.initials: C
authors.lastname: Schneider
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shen
authors.forename: Antony B
authors.initials: AB
authors.lastname: Holmes
authors.forename: Manu
authors.initials: M
authors.lastname: Setty
authors.forename: Christina
authors.initials: C
authors.lastname: Leslie
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D020413:3' Untranslated Regions; C084103:BCL6 protein, human; C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; C524942:MIRN155 microRNA, human; C575475:MIRN361 microRNA, human; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase