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Gene enhancers in lymphoma

Epigenetic processes can regulate which part of the DNA is active in each cell. Understanding how epigenetics may interfere with cancer development is an area of active investigation.
Gene enhancers in lymphoma
B-cell differentiation is a complex process in which epigenetic changes such as DNA methylation and histone modifications are central to gene expression regulation. Disturbances in epigenetic processes can lead to the development of B-cell malignancies. Interestingly, most DNA methylation changes do not occur in promoter regions as initially envisaged but at intra- and intergenic loci, which are enriched for enhancers.

Mantle cell lymphoma (MCL) is a specific type of lymphoma with an aggressive clinical course and poor clinical outcome. MCLs carry a fusion of a part of chromosome 11 and chromosome 14 that leads to the activation of the protein cyclin D1. In addition, activation of the protein SOX11 has been implicated in aggressive MCL cases. So far, little is known about the epigenetic alterations underlying MCL.

The scope of the EU-funded DNAMETHYLOOPMCL (Of DNA methylation and looping of distant regulatory elements in mantle cell lymphoma) project was to study the epigenetic and the 3D genomic landscape in MCL. The idea was to discover unknown DNA regions whose deregulation might contribute to the development and/or aggressiveness of this lymphoma.

Researchers mapped the DNA methylation landscape of over 80 MCL samples alongside the histone modification landscape in some of them. Compared to normal lymphocytes, the hypomethylated DNA areas in MCL samples were enriched for enhancer regions. Interestingly, one of these regions was located within proximity of the SOX11 gene and loops in 3D space to the SOX11 gene, most likely serving as an enhancer element of this MCL related oncogene.

Overall, the results of the current study demonstrated that DNA hypomethylation in MCL could be used to detect genomic regions whose activation contributes to disease development. Furthermore, DNAMETHYLOOPMCL emphasised the need for 3D genome structure analysis in enhancer identification as enhancers do not necessarily activate their most neighbouring gene. In general, the same approach could be utilised to discover other regulatory regions to better understand the biology of this aggressive disease.

The results of the current study were published in November 2016 in Cancer Cell as an open access article that is available online.

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