In the Venn diagram of epigenetics and cancer biology, EZH2 sits perfectly in the overlap. This methyltransferase is responsible for tri-methylation of lysine 27 on histone 3 (H3K27me3) but is also an oncogene, mutated in a variety ofhumancancers. H3K27me3 is a marker of inactive chromatin domains, specifically topologically associating domains (TADs), and has been linked to the silencing of tumor suppressors. Luckily, the Venn diagram of talent and epigenetics researchers is pretty much a circle, and the overlapping efforts from the labs of Giovanni Ciriello and Elisa Oricchio (Lausanne, Switzerland) have uncovered a novel way that EZH2 contributes to oncogenesis.
This talented team took advantage of a known gain-of-function mutation in EZH2 (EZH2Y646X) that contributes to genome-wide increases in H3K27me3 levels, ultimately resulting in transcriptional repression. This kind of project requires the whole of the epigenetics toolbox: they generated mutant and wild type EZH2 lymphoma cell lines and utilized Hi-C chromatin maps to investigate alterations in chromatin structure, followed by ChIP-seqof H3K27me3 to investigate methylation differences in TADs, as well as RNA-seq to quantify expression levels.
Here’s a tad-bit of what they found:
- Mutant EZH2 does not significantly alter chromatin structure or the ability to form TADs
- In the EZH2Y646Fcell line, H3K27me3 is enriched within specific TADs and results in down-regulation of genes within those TADs
- Many of these down-regulated genes are heavily involved in B-cell differentiation and proliferation
- Aberrant H3K27me3 by mutant EZH2 modulates promoter-promoter interactions, and results in silencing of multiple tumor suppressor genes within a single TAD
- Co-knockdown of tumor suppressor genes within a single TAD results in a synergistic tumor promoting effect
- Pharmacological inhibition of EZH2 rescues the expression of the tumor suppressors
Mutant EZH2’s epigenetic alterations ultimately affect intra-TAD interactions and gene expression, leading to the down-regulation of multiple tumor suppressors in concert. Future work will investigate if these traits are selected for during oncogenesis, or predetermined, and additionally investigate potential tumor suppressor TADs.
If EZH2 fits your Venn diagram of research interests, head over to Nature Genetics, January 2019