Researchers have explored how cancer cells re-organise the 3D structure of their DNA to enhance oncogene activity.
In order to establish and maintain oncogenic transcriptional programs, cancer cells must modify their epigenome. Mutations that affect the activity of epigenetic modifiers are common across tumour types. The 3D structural organisation of chromatin is underpinned by architectural proteins, like CTCF and cohesion. They are also impacted by histone modifications that segregate chromatin into compartments. In cancer cells, changes in DNA methylation patterns can reduce the ability for such architectural proteins to bind to chromatin. This results in spurious interactions and thus can enable aberrant oncogene expression. Mutated chromatin modifiers can also alter distribution of histone marks. In addition, tumour development is often accompanied by chromosomal alterations that cause rearrangements of coding and non-coding regions.
Oncogenic enhancer activity can be found in the absence of chromosomal alternations. In fact, researchers have found it to be associated with increased and/or spreading of H3K27ac at enhancer regions. However, how the chromatin conformation of enhancer-promoter interactions is impacted by this alteration is unclear.
Hijacking 3D structure
In this paper, published in Nature Genetics, researchers investigated how changes in H3K27ac alter chromatin interactions in cancer cells by repositioning enhancer regions and thus changing local interactions between enhancers and promoters. The team specifically developed a novel algorithm approach called Calder to track how genomic regions are positioned with respect to each other. Using Calder, the researchers were able to track regions of chromatin that moved from one area of the nucleus to another due to changing epigenetic marks.
By comparing normal and lymphoma B cells, the team found that enhancer-promoter-interacting regions had different conformations according to the local abundance of H3K27ac. In lymphoma cells, they discovered that specific epigenetic changes caused chromatin regions to be repositioned in different areas of the nucleus. In turn, this led to novel local interactions that resulted in the overexpression of oncogenes.
They also found that chromosomal translocations assumed a 3D structure that was different from normal copies. These changes of 3D structure corresponded to different epigenetic marks and induced high expression of tumour supporting genes.
Overall, these findings show that H3K27ac dynamics impact the frequency of interactions between regulatory regions and can lead to chromatin configurations that sustain oncogene expression.
Image credit: By 7activestudio – canva.com