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Oncogene. 2015 Jan 8;34(2):246-56. doi: 10.1038/onc.2013.535. Epub 2013 Dec 23.

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

Author information

1
1] Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC) and Departamento de Biología Molecular, Universidad de Cantabria, CSIC, SODERCAN, Santander, Spain [2] Servicio de Hematología, Hospital U. Marqués de Valdecilla, and IFIMAV-FMV, Santander, Spain.
2
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC) and Departamento de Biología Molecular, Universidad de Cantabria, CSIC, SODERCAN, Santander, Spain.
3
Servicio de Hematología, Hospital U. Marqués de Valdecilla, and IFIMAV-FMV, Santander, Spain.
4
Department of Cancer Studies and Molecular Medicine and MRC Toxicology Unit, University of Leicester, Leicester, UK.

Abstract

BCL6 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.

PMID:
24362533
DOI:
10.1038/onc.2013.535
[Indexed for MEDLINE]
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