Figure 3

Senescence-associated hypomethylation is enriched in lamina-associated domains. DNAm profiles of fibroblasts at early and late passage (MethylCap-seq) were compared to previously published data on H3K27me3 [30], H3K4me3 [30], H3K4me1 [30], H3K9me3 [30], and lamina-associated domains (LADs) [29] in fibroblasts. Non-methylated DNA was particularly associated with the histone mark H3K9me3 and LADs, whereas H3K27me3, H3K4me3, and H3K4me1 were significantly reduced in these regions. RPKM signals are exemplarily depicted for a region in chromosome 16 (A). Distributions of average RPKM levels of H3K27me3 (B), H3K4me3 (C), H3K4me1 (D), and H3K9me3 (E) in 1,000-bp windows around DMRs are shown. Average signal intensity of DNAm was significantly lower inside LADs than outside LADs (Mann-Whitney test of equal means) (F). A particular sharp decline of DNAm level was observed at the border of LADs (in all samples) (G). Senescence-associated DMRs were then correlated with LADs. The proportion of senescence-associated (SA) hypermethylation was significantly decreased in LADs while SA-hypomethylation was highly significantly increased in LADs as compared to randomly selected regions (two-tailed Fisher’s Exact test) (H).