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Title

Novel CTCF binding at a site in exon1A of BCL6 is associated with active histone marks and a transcriptionally active locus

AuthorsBatlle-López, Ana; Cortiguera, María G. ; Rosa-Garrido, Manuel ; Blanco, Rosa ; Cerro, Elida del; Torrano, Verónica; Wagner, Simon D.; Delgado, M. Dolores
KeywordsCTCF
Germinal centre
Lymphoma
BCL6
Epigenetics
Issue Date2015
PublisherNature Publishing Group
CitationOncogene 34(2): 246-256 (2015)
AbstractBCL6 is a zinc-finger transcriptional repressor, which is highly expressed in germinal centre B-cells and is essential for germinal centre formation and T-dependent antibody responses. Constitutive BCL6 expression is sufficient to produce lymphomas in mice. Deregulated expression of BCL6 due to chromosomal rearrangements, mutations of a negative autoregulatory site in the BCL6 promoter region and aberrant post-translational modifications have been detected in a number of human lymphomas. Tight lineage and temporal regulation of BCL6 is, therefore, required for normal immunity, and abnormal regulation occurs in lymphomas. CCCTC-binding factor (CTCF) is a multi-functional chromatin regulator, which has recently been shown to bind in a methylation-sensitive manner to sites within the BCL6 first intron. We demonstrate a novel CTCF-binding site in BCL6 exon1A within a potential CpG island, which is unmethylated both in cell lines and in primary lymphoma samples. CTCF binding, which was found in BCL6-expressing cell lines, correlated with the presence of histone variant H2A.Z and active histone marks, suggesting that CTCF induces chromatin modification at a transcriptionally active BCL6 locus. CTCF binding to exon1A was required to maintain BCL6 expression in germinal centre cells by avoiding BCL6-negative autoregulation. Silencing of CTCF in BCL6-expressing cells reduced BCL6 mRNA and protein expression, which is sufficient to induce B-cell terminal differentiation toward plasma cells. Moreover, lack of CTCF binding to exon1A shifts the BCL6 local chromatin from an active to a repressive state. This work demonstrates that, in contexts in which BCL6 is expressed, CTCF binding to BCL6 exon1A associates with epigenetic modifications indicative of transcriptionally open chromatin.
Publisher version (URL)http://dx.doi.org/10.1038/onc.2013.535
URIhttp://hdl.handle.net/10261/130598
DOI10.1038/onc.2013.535
Identifiersdoi: 10.1038/onc.2013.535
e-issn: 1476-5594
issn: 0950-9232
Appears in Collections:(IBBTEC) Artículos
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