Loss of heterochromatin structure has been proposed as a unifying theory of ageing across cell-types and species, whereby genes or endogenous retroviral elements which should be silenced get aberrantly expressed causing cellular dysfunction. Evidence for this theory comes particularly from studies of the lifespan of model organisms. Here, we investigate the causal role of heterochromatin loss in immune dysfunction, a characteristic of ageing which leaves elderly individuals more susceptible to infections and less responsive to vaccinations.
To do this, we use genetic deletion of the mammalian Suppressor of Variegation-39 Homologues Suv39h1 and Suv39h2, the histone methyltransferase enzymes responsible for the H3K9me3 mark of constitutive heterochromatin. We show that the immune system is remarkably tolerant of heterochromatin loss. However, complete loss of heterochromatin structure precipitates a premature ageing phenotype.
Unexpectedly, RNAseq analysis reveals global gene repression following heterochromatin loss. Comprehensive molecular analyses (in situ HiC, H3K9me3-, H3K27ac-, and LaminB1-ChIP) reveal that this gene repression is associated with reduced topologically-associated domains (TADs), loss of higher-order TAD-TAD interactions, and a decrease in lamina-associated domains (LADs), features recapitulated by 3-dimensional modelling of genome structure. Together, these results reveal that heterochromatin structure is critical for higher-order chromatin organisation, not just simple gene silencing, and that it is the loss of this global organisation of the genome that is associated with immune ageing.