The Senescent Methylome and its relationship with cancer, ageing, and germline genetic variation in humans (methylation experiment 1)

Cellular senescence is a stable arrest of proliferation and is considered a key component of processes associated with carcinogenesis and other ageing-related phenotypes. However, till now, biological markers that define senescence on a genome-wide scale have been limited. Here, we report a DNA methylomic analysis of actively dividing and deeply senescent normal human epithelial cells, identifying 3,852 senescence-associated differentially methylated positions (senDMPs). We find that this human senDMP signature is positively and significantly correlated with both cancer and ageing-associated methylomic dynamics. We also identify germline genetic variants, including those associated with the p16INK4A locus, that are associated with the presence of in vivo senDMP signatures. Importantly, we also demonstrate that the senDMP signature can be effectively reversed in a newly-developed protocol of transient cellular rejuvenation. The senDMP signature has significant potential for understanding some of the key (epi)genetic etiological factors that lead to cancer and age-related diseases in humans. Bisulphite converted DNA from the HMECs at early passage (EP), deep senescence (DS), deep senescence + p16 siRNA (DS+p16siRNA) at two different time points and FACS for cell cycle at EP were hybridised to the Illumina Infinium 450k Human Methylation Beadchip