title: BCL6 promoter interacts with far upstream sequences with greatly enhanced activating histone modifications in germinal center B cells.
abstract: BCL6 encodes a transcriptional repressor that is essential for the germinal center (GC) reaction and important in lymphomagenesis. Although its promoter has been well studied, little is known concerning its possible regulation by more distal elements. To gain such information, we mapped critical histone modifications associated with active transcription within BCL6 as well as far upstream sequences at nucleosomal resolution in B-cell lines and in normal naive and GC B cells. Promoter-associated and intronic CpG islands (CGIs) in BCL6 showed a reciprocal pattern of histone modifications. Gene expression correlated with a paradoxical loss from the intronic CGI of histone H3 lysine-4 trimethylation, normally associated with transcription, suggesting that the intronic CGI may interfere with transcription. In an approximately 110-kb region extending 150-260 kb upstream of BCL6, highly active histone modifications were present only in normal GC B cells and a GC B-cell line; this region overlaps with an alternative breakpoint region for chromosomal translocations and contains a GC-specific noncoding RNA gene. By chromosome conformation capture, we determined that the BCL6 promoter interacts with this distant upstream region. It is likely that transcriptional enhancers in this region activate BCL6 and overcome strong autorepression in GC B cells.
authors.affiliation: Department of Pathology and Immunology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Himabindu
authors.initials: H
authors.lastname: Ramachandrareddy
authors.forename: Alyssa
authors.initials: A
authors.lastname: Bouska
authors.forename: Yulei
authors.initials: Y
authors.lastname: Shen
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.forename: Angie
authors.initials: A
authors.lastname: Rizzino
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.forename: Timothy W
authors.initials: TW
authors.lastname: McKeithan
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017124:Conserved Sequence; D003598:Cytoskeletal Proteins / Q000235:genetics; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology; D044127:Epigenesis, Genetic; D015870:Gene Expression; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism*; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007438:Introns; D060588:LIM Domain Proteins; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology
chemical_list: C084103:BCL6 protein, human; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D006657:Histones; D060588:LIM Domain Proteins; C103594:LPP protein, human; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins