Abstract
Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here, we showed that
LINE-1
(
Long Interspersed Nuclear Element-1; L1
) RNA accumulation was an early event in both typical and atypical human progeroid syndromes.
L1
RNA negatively regulated the enzymatic activity of the histone-lysine
N
-methyltransferase SUV39H1 (suppression of variegation 3-9 homolog 1), resulting in heterochromatin loss and onset of senescent phenotypes in vitro. Depletion of
L1
RNA in dermal fibroblast cells from patients with different progeroid syndromes using specific antisense oligonucleotides (ASOs) restored heterochromatin histone 3 lysine 9 and histone 3 lysine 27 trimethylation marks, reversed DNA methylation age, and counteracted the expression of senescence-associated secretory phenotype genes such as
p16
,
p21
,
activating transcription factor 3
(
ATF3
),
matrix metallopeptidase 13
(
MMP13
),
interleukin 1a
(
IL1a
),
BTG anti-proliferation factor 2
(
BTG2
), and
growth arrest and DNA damage inducible beta
(
GADD45b
). Moreover, systemic delivery of ASOs rescued the histophysiology of tissues and increased the life span of a Hutchinson-Gilford progeria syndrome mouse model. Transcriptional profiling of human and mouse samples after
L1
RNA depletion demonstrated that pathways associated with nuclear chromatin organization, cell proliferation, and transcription regulation were enriched. Similarly, pathways associated with aging, inflammatory response, innate immune response, and DNA damage were down-regulated. Our results highlight the role of
L1
RNA in heterochromatin homeostasis in progeroid syndromes and identify a possible therapeutic approach to treat premature aging and related syndromes.
LINE-1
RNA nuclear accumulation is an early event in progeroid syndromes and leads to heterochromatin erosion and onset of senescent phenotypes.
Linking LINE-1 to premature aging syndromes
Heterochromatin condensation suppresses repetitive and transposable elements, including long interspersed nuclear element (LINE) retrotransposons, but is lost during aging, leading to derepression of these LINE elements. However, the consequences of this derepression are not fully understood. Here, Della Valle
et al.
studied LINE-1 in typical and atypical progeroid syndromes. Nuclear
LINE-1
RNA expression occurred early in progeroid cells, resulting in suppression of the histone-lysine
N
-methyltransferase SUV39H1 activity, leading to heterochromatin loss and senescent phenotypes. Depletion of
LINE-1
RNA using antisense oligonucleotides restored heterochromatin epigenetic marks and decreased the expression of senescence-associated genes in human cells and in a mouse model of Hutchinson-Gilford progeria syndrome, resulting in increased life span. These findings suggest
LINE-1
RNA as a therapeutic target for premature aging syndromes.