Assembling tomatoes, mozzarella, and basil into the formidable Insalata Caprese is a straightforward affair and a quick shake, and pour can make tequila, triple sec, and lime juice combine into the sublime margarita cocktail. However, no one has yet managed to fit mitochondrial dysfunction, telomere attrition, and histone acetylation into a dish of data worthy of a Michelin star (or three!).
However, in the search for a worthy recipe, researchers from the lab of Narayan G. Avadhani (University of Pennsylvania, Philadelphia, PA, USA) recently served up an interesting epigenetic entrée: that in response to mitochondrial dysfunction, mouse muscle cells upregulate and activate heterogeneous ribonuclear protein (hnRNP) A2, a recently outed histone lysine acetyltransferase (KAT) for histone H4 at lysine 8 of (H4K8).
Now, scrumptious new experimentation from Guha and Colleagues builds on their tasty starter to report a gastronomic method to combine three different scientific ingredients into a dish to remember:
- Initial studies employing Southern hybridization and quantitative fluorescent in situ hybridization (Q-FISH) analysis in the C2C12 immortalized mouse myoblast cell line confirmed that telomere shortening occurs as a response to mitochondrial stress brought on by either ethidium bromide treatment or mitochondrial (mt)DNA depletion (via 2’3′-dideoxycytidine (ddC) treatment)
- The authors observed the expected increase in hnRNPA2 expression in response to mitochondrial stress and also noted a link between telomere attrition and activation of the DNA damage response at telomeres in response to mitochondrial dysfunction
- Analysis of myoblasts from a mouse model with a mutation in a mitochondrial inner membrane protein (MPV17−/− mice) confirmed that mitochondria loss leads to the upregulation of hnRNPA2 and telomere attrition
- HnRNPA2 displays single-stranded telomeric repeat sequence binding activity and chromatin immunoprecipitation (ChIP) assays discovered a higher level of HnRNPA2 binding at the telomeres in cells with dysfunctional mitochondria
- Higher levels of HnRNPA2-induced H4K8 acetylation of telomere-associated histones leads to shorter telomeres independent of cell proliferation rates, linking higher acetylation with telomere attrition as suggested by a previous study
- Alterations to telomere length in response to mitochondrial dysfunction depend on histone acetylation status, as KAT mutant hnRNPA2 proteins lacking KAT activity partially rescue telomere length
Overall the authors believe that their delicious data highlights mitochondrial stress-induced hnRNPA2-mediated H4K8 acetylation as a signal for telomere shortening; however, just how acetylation of telomeric histones leads to telomere shortening has been left as part of an unfinished recipe open to another shift of chefs to whip up an answer.
Fancy a bite? Well, head over to PLoS One, November 2018 and gorge on this epigeneticists’ delight!