Cancer: Oncogene brought into the loop

Abstract

Analysis of the 3D structure of DNA in tumour cells reveals how mutations in the IDH1 gene, and associated changes in methyl groups attached to DNA, elevate the expression of cancer-promoting genes.

Figure 1. Breaking down boundaries to cancer

Structural boundaries between regions of chromatin (the complex of DNA and proteins in which DNA is packaged in the nucleus) define loops called topologically associated domains (TADs), within which gene activity is coordinated. DNA binding by the insulator protein CTCF separates these domains. Flavahan et al. provide evidence that CTCF insulation prevents the activation of oncogenes (genes whose hyperactivity promotes cancer) by distant enhancer elements from different TADs. The authors find that mutations in the gene IDH1 increase the number of methyl groups that are attached to CTCF binding sites, reducing CTCF–DNA binding. This breaks down the TAD border structure, allowing aberrant association between enhancers and the promoter regions of oncogenes. Oncogene expression is subsequently amplified, leading to cancer.