We recently advised our readers to “think different” when it came to the epigenetic control of maintenance in alternative lengthening of telomeres (ALT) cells, and now, a team of “out-of-the-box” thinkers from the lab of Jérôme Déjardin (Université de Montpellier, France) have described an unconventional link between ALT and telomeric heterochromatin formation.
Previous results have strongly indicated that SUV39H-mediated heterochromatin formation prevented telomere maintenance in ALT cells and that ALT telomeric chromatin presents in a decondensed H3K9me3-poor state. However, a recent meta-analysis established that ALT cell telomeres possess high levels of H3K9me3, suggesting that there may be an alternative narrative and that heterochromatin may promote the maintenance of telomeres in ALT cells.
To solve this off-beat problem, Gauchier and colleagues employed various gene-knockouts and an avant-garde quantitative locus-specific proteomic technique – proteomics of isolated chromatin segments (PICh) combined with stable isotope labeling with amino acids in cell culture (SILAC) – to evaluate telomeric status under a changing heterochromatic environment. The authors studied wild type and Suv39h-knockout mouse embryonic stem cells (mESCs) as models as they display an ALT-like phenotype, and later confirmed their results in human ALT cancer cells.
Excitingly, the results of this alternate look at telomere maintenance failed to conform to most accepted hypotheses about the function of silent, heterochromatic regions!
- While multiple studies link ALT to the loss of telomeric heterochromatin, the team establish that ALT normally results from telomeric heterochromatin formation via the activity of the H3K9me3-specific histone methyltransferase SET Domain Bifurcated 1 (Setdb1)
- Knockout of the Suv39h H3K9 histone methyltransferase in mESCs prompts an indirect increase in telomeric heterochromatin via the displacement of the heterochromatic protein HP1 from pericentromeric heterochromatin
- HP1 then relocalizes to the telomeres, stimulates Setdb1 recruitment, and increases H3K9me3 formation
- The induction of telomeric heterochromatin formation prompts the appearance of ALT features
- Features include promyelocytic leukemia (PML) body formation, TERRA long non-coding RNA transcription, recombination factor recruitment and, most importantly, transcriptional elongation at telomeres
- Overall, the authors reveal that atypical heterochromatin formation (the presence of H3K9me3 and the transcriptional elongation-associated H3K36me3 modification) at telomeres is “recombinogenic” and stimulates transcriptional elongation, thereby promoting ALT
- In human ALT cancer cells, SETDB1 loss disrupts telomeric heterochromatin and inhibits ALT
- Therefore, the authors propose histone methyltransferase inhibitors or heterochromatin-disrupting molecules as novel therapeutic strategies for disrupting ALT in human cancers
Overall, the unexpected results from this study now establish that heterochromatin finds a way to lengthen telomeres by promoting ALT. What further surprises will epigenetic studies of the ALT phenotype bring to light?