The mysteries of the epiregulome need to be tackled head-on if we are to get new precision treatments for blood cancers says Lisa Russell. Here she takes us through the promise of super-enhancer biology and what it means for cancer…
To continue to improve outcomes and quality of life for patients with haematological malignancies, we must look beyond the information encoded in DNA and past the well-mapped landscape of known genetic aberrations.
I believe the next frontier could lie not in the coding sequence itself, but in the dynamic regulatory networks of the non-coding genome that orchestrate gene expression – the epiregulome.
With more than 200 cell types comprising the human body, precise lineage-specific gene regulation is fundamental to maintaining cellular diversity. Recent breakthroughs have revealed that the guardians of cell identity often reside in the vast non-coding regions of the genome where clusters of enhancers – aptly named super-enhancers – exert extraordinary regulatory control. These powerful elements, first described in the baculovirus genome and later in mouse embryonic stem cells, coordinate the high-fidelity expression of genes that define cell identity.
With great power comes vulnerability. Super-enhancers ensure expression of cell identity genes and tumour suppressors, protecting healthy cells from malignant transformation. However, this same power renders them susceptible to hijacking by cancer cells.
But with great power comes vulnerability. Super-enhancers ensure robust and sustained expression of cell identity genes and tumour suppressors, protecting healthy cells from malignant transformation. However, this same power renders them susceptible to hijacking by cancer cells. In malignancies such as acute lymphoblastic leukaemia, super-enhancers activate proto-oncogenes, changing their original role and turning from genomic guardians into agents of disease.
Credit: by Cancer Research UK