On the list of “first world problems”, having your tablet or e-reader break is certainly an annoyance; you might get stuck watching bad in-flight movies or have to wait a bit longer to see what happens in the big plot twist. But the story might be in the horror genre if it’s your histone reader that malfunctions. In the latest page-turner from the labs of David Allis (Rockefeller University, USA) and Hong Wen (Van Andel Research Institute, USA), the protagonist is a histone reader known as the eleven-nineteen-leukemia (ENL) protein, and the plot follows its dysregulation and the impact on cell fate.
The ENL protein is part of the larger super elongation complex (SEC) that drives transcriptional elongation, and ENL has been linked to oncogenic gene expression in leukemia. ENL functions as a reader by binding acetylated histones through a conserved YEATS domain and recently, mutations in this domain were identified in ~5% of patients with a form of pediatric kidney cancer known as Wilms’ tumor. This discovery prompted the collaborative team to investigate the role of mutant ENL in the development of Wilms’ tumor.
Here’s the short synopsis:
- Cells expressing ENL with a YEATS domain mutation show increased expression of genes involved in embryonic kidney differentiation, and develop undifferentiated nephron structures in a three-dimensional nephrogenesis assay
- Both of these phenotypes are consistent with Wilms’ tumor
- ChIP-seq mapping shows no difference in genomic localization of mutant ENL, but did reveal increased ENL occupancy at a subset of sites
- CDK9 (an SEC component) is also enriched at these sites, and both are required for an observed increase in gene activation
- The acetyl-lysine-binding activity of mutant ENL is still required for chromatin targeting and does not contribute to the increased ENL accumulation
- Tumorigenic ENL mutations accumulate at loci via increased self-association, and these higher-order interactions are dynamic and multivalent
The tumorigenic ENL story unveils a mechanism by which chromatin readers can alter gene expression and ultimately impact cell fate. Importantly, a better understanding of the mutant ENL reader may allow for the development of therapeutic interventions for Wilms’ tumor patients; hopefully further characterization of mutant ENL dynamics will follow in a sequel!
Read the full story (on whatever device you like) in Nature, December 2019.