Investigating the role of DNA methylation in the failing and in the ageing heart

Ageing is the greatest risk factor for heart failure. Heart muscle cells (cardiomyocytes, CMs) experience ageing-associated alterations leading to a lower functional output, caused by (among others) maladaptive  remodelling of the myocardium, including hypertrophy of individual cardiomyocytes. CMs are long-lived (decades) and have limited proliferative capacity.  Transcriptional variation (heterogeneity) between CMs increase with age, with potentially detrimental consequences for heart function. Not only does this reflect dysregulation of gene transcriptional control in individual cells, it also likely reflects changes in CM subpopulations/states, such as the ratio of maladapted hypertrophic- to normal CMs. Transcription is regulated in part by DNA methylation (DNAm) (an epigenetic modification). Curiously, global DNAm decreases with age. Our data show that the expression of the TET2 DNA demethylase increases with age, with profound inter-CM heterogeneity. We hypothesize that changes in DNAm patterns induce transcriptional remodelling underlying dysfunction during normal ageing of CMs. We further propose that the increased variability in transcriptomes between CMs in ageing is mediated by stochastic  alterations in DNAm brought about by increased TET2 expression.