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

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.

Hyperglycaemia aggravates periodontal inflamm‐aging by promoting SETDB1‐mediated LINE‐1 de‐repression in macrophages

“…Endogenous LINE‐1 de‐repression occurs in both pathological (Della Valle et al, 2022) and physiologically senescent cells (De Cecco et al, 2019; Simon et al, 2019; Van Meter et al, 2014). In addition to its involvement in replicative senescence, LINE‐1 activation is also observed during stress‐induced senescence (Farkash et al, 2006; Kale et al, 2005) (Stribinskis & Ramos, 2006) (Shi et al, 2021) (Lucchinetti et al, 2006).…”

“…Additionally, accumulation of LINE‐1 complementary DNA (cDNA) and widespread expression of the LINE‐1 encoded protein ORF1p in the cytoplasm of deeply senescent cells cause sterile inflammation by activating the type I interferon (IFN‐I) response (De Cecco et al, 2019; Simon et al, 2019). Knockdown of LINE‐1 rescues the progeria phenotype and extends the lifespan of mice (Della Valle et al, 2022). However, the effects of high ambient glucose levels on LINE‐1 activation remain unclear.…”

Retroelement-Age Clocks: Epigenetic Age Captured by Human Endogenous Retrovirus and LINE-1 DNA methylation states

“…Emerging evidence suggests a correlation between aging and the reactivation of specific retroelements, primarily LINEs and HERV-K-derived retrovirus like particles (RVLPs). Prior work has shown that the transcriptional derepression of LINEs in immune cells cells triggers interferon production to contribute to inflammaging ( 7 , 75–77 ). Recent findings have suggested a key role of the endogenous retrovirus HERV-K (HML-2) activation in cellular senescence and tissue aging( 6 ).…”

An Epigenetic LINE-1-Based Mechanism in Cancer

“…The implications of these findings in the genesis of cancer will be discussed in depth in the next section. Remarkably, a recent study in the context of progeroid syndromes, which are basically caused by lamina defects, has depicted a novel role of LINE-1 RNA transcription in influencing chromatin organization, cell proliferation, DNA damage, and gene expression profiles [ 96 ].…”