LINE-1 RNA is causative of heterochromatin erosion and target for amelioration of senescent phenotypes in progeroid syndromes

Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. In higher eukaryotes, constitutive heterochromatin is mostly segregated at the nuclear periphery, where the interaction with the nuclear lamina makes the genome more resistant to transcription. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here we show that LINE-1 (L1) RNA accumulation is an early event in both typical and atypical progeroid syndromes. Depletion of L1 RNA in cells from different progeroid syndrome patients using specific antisense oligonucleotides (ASO) restores the levels of heterochromatin epigenetic marks, reverses DNA methylation age and counteracts the expression of senescence-associated genes. Moreover, proteome profiling involved in senescence phenotype was partially restored upon depletion of LINE-1 RNA in both Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner syndrome (WRN-/-).