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Ikaros and RAG-2-mediated antisense transcription are responsible for lymphocyte-specific inactivation of NWC promoter.

ABSTRACT: Recombination activating gene-2 (RAG-2) and NWC are strongly evolutionarily conserved overlapping genes which are convergently transcribed. In non-lymphoid cells the NWC promoter is active whereas in lymphocytes it is inactive due to the DNA methylation. Analysing the mechanism responsible for lymphocyte-specific methylation and inactivation of NWC promoter we found that Ikaros, a lymphocyte-specific transcription factor, acts as a repressor of NWC promoter--thus identifying a new Ikaros target--but is insufficient for inducing its methylation which depends on the antisense transcription driven by RAG-2 promoter. Possible implications of these observations for understanding evolutionary mechanisms leading to lymphocyte specific expression of RAG genes are discussed.

SUBMITTER: Laszkiewicz A

PROVIDER: S-EPMC4157847 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Ikaros and RAG-2-mediated antisense transcription are responsible for lymphocyte-specific inactivation of NWC promoter.

Laszkiewicz Agnieszka A Bzdzion Łukasz Ł Kasztura Monika M Snieżewski Lukasz L Janik Sylwia S Kisielow Paweł P Cebrat Małgorzata M

PloS one 20140908 9

Recombination activating gene-2 (RAG-2) and NWC are strongly evolutionarily conserved overlapping genes which are convergently transcribed. In non-lymphoid cells the NWC promoter is active whereas in lymphocytes it is inactive due to the DNA methylation. Analysing the mechanism responsible for lymphocyte-specific methylation and inactivation of NWC promoter we found that Ikaros, a lymphocyte-specific transcription factor, acts as a repressor of NWC promoter--thus identifying a new Ikaros target- ...[more]

PMID: 25198102

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Project description:BackgroundLeucine-rich repeat C4 protein (LRRC4) is a new member of the leucine-rich repeat (LRR) superfamily. It is not only a brain-specific gene but also a novel candidate for tumor suppression. LRRC4 inactivation is commonly found in glioma cell lines and primary glioma biopsies. However, little is known about the mechanism controlling LRRC4 expression. In a previous study, we did not find any genetic alteration in LRRC4 in primary glioma, which led us to explore an alternative mechanism underlying this phenomenon.MethodsIn the present paper, we cloned the LRRC4 promoter with characteristics of a CpG island by luciferase reporter assay. Then, the CpG methylation status around the LRRC4 promoter region in glioma cell lines and primary gliomas was examined by methylation-specific PCR and bisulfite DNA sequencing. In order to demonstrate a functional association between LRRC4 promoter methylation and its gene inactivation, we performed DNA demethylation analysis with two human glioma cell lines using methylation-specific PCR and RT-PCR.ResultsThe sequence spanning positions -835 to -293 relative to the translation start site was identified as the LRRC4 promoter; this sequence is a TATA- and CAAT- less, high GC content region. It was found that LRRC4 promoter activity is strongly suppressed after treatment with SssI methylase in vitro. Furthermore, LRRC4 promoter methylation was observed by methylation-specific PCR in two glioma cell lines and all 30 primary glioma specimens, but not in normal brain tissue. Bisulfite DNA sequencing showed that most of the CpG sites were located around the LRRC4 promoter methylated in glioma cells and tissues, but not in normal brain tissue. In addition, the methylase inhibitor 5-Aza-2'-deoxycytidine could induce LRRC4 mRNA expression and LRRC4 promoter partial demethylation in SF126 and SF767 glioma cells.ConclusionMethylation-mediated inactivation of LRRC4 is a frequent and glioma-specific event, and it may be a potential biomarker for diagnosis or prognosis, or serve as a therapeutic target.

Dataset Information

Ikaros and RAG-2-mediated antisense transcription are responsible for lymphocyte-specific inactivation of NWC promoter.

Publications

Ikaros and RAG-2-mediated antisense transcription are responsible for lymphocyte-specific inactivation of NWC promoter.

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