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

Della Valle, Francesco; Reddy, Pradeep; Yamamoto, Mako; Liu, Peng; Saera-Vila, Alfonso; Bensaddek, Dalila; Zhang, Huoming; Prieto Martinez, Javier; Abassi, Leila; Celii, Mirko; Ocampo, Alejandro; Nuñez Delicado, Estrella; Mangiavacchi, Arianna; Aiese Cigliano, Riccardo; Rodriguez Esteban, Concepcion; Horvath, Steve; Izpisua Belmonte, Juan Carlos; Orlando, Valerio

doi:10.1126/scitranslmed.abl6057

Cited by 127Telomeres, Telomerase, and SenescenceNuclear Structure and FunctionGenomics and Chromatin Dynamics

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

Della Valle, Francesco, Reddy, Pradeep, Yamamoto, Mako, Liu, Peng, Saera-Vila, Alfonso, Bensaddek, Dalila, Zhang, Huoming, Prieto Martinez, Javier, Abassi, Leila, Celii, Mirko, Ocampo, Alejandro, Nuñez Delicado, Estrella, Mangiavacchi, Arianna, Aiese Cigliano, Riccardo, Rodriguez Esteban, Concepcion, Horvath, Steve, Izpisua Belmonte, Juan Carlos, Orlando, Valerio·2022·Science Translational Medicine

DOI 10.1126/scitranslmed.abl6057

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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 chro…

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Epigenetic derepression of LINE-1 RNA inhibits the epigenetic reader Suv39H1,2 resulting in global reduction of H3K9me3 and heterochromatin.
“Mechanistically, epigenetic derepression of LINE-1 RNA inhibits the epigenetic reader Suv39H1,2 resulting in global reduction of H3K9me3 and heterochomatin 71 , while reverse transcription of LINE-1 RNA results in double-stranded cDNA that activates the cGAS/STING/interferon pathway 72 .”
From Hallmarks of aging: An expanding universe (2023) · cites this paper as [71]
In vivo targeting of retrotransposons with antisense oligonucleotides increases the lifespan of progeroid mice.
“Moreover, in vivo targeting of retrotransposons with antisense oligonucleotides increases the lifespan of progeroid mice 71 .”
From Hallmarks of aging: An expanding universe (2023) · cites this paper as [71]
Genomic mosaicism by retrotransposition of LINE-1 elements has been associated with the neuronal genome and the derepression of LINE-1 elements has been associated with senescence.
“Indeed, genomic mosaicism by retro transposition of LINE-1 elements has been associated with the neuronal genome and the derepression of LINE-1 elements has been associated with senescence129–131.”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [131]

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Authors: Della Valle, F., Reddy, P., Yamamoto, M., Liu, P., Saera-Vila, A., Bensaddek, D., Zhang, H., Prieto Martinez, J., Abassi, L., Celii, M., Ocampo, A., Nuñez Delicado, E., Mangiavacchi, A., Aiese Cigliano, R., Rodriguez Esteban, C., Horvath, S., Izpisua Belmonte, J. C., & Orlando, V.
Affiliations: King Abdullah University of Science and Technology (KAUST), Biological Environmental Sciences and Engineering Division BESE, KAUST Environmental Epigenetics Program, Thuwal, Saudi Arabia.
Salk Institute for Biological Studies (US)
King Abdullah University of Science and Technology (SA)
Sequentia Biotech, Carrer Comte D’Urgell 240, Barcelona 08036, Spain.
Salk Institute for Biological Studies, La Jolla, CA, USA.
Thuwal, Saudi Arabia.
Altos Labs (US)
Corresponding author: Reddy, Pradeep
Orlando, Valerio
ORCID: Della Valle, Francesco
Reddy, Pradeep
Liu, Peng
Saera-Vila, Alfonso
Bensaddek, Dalila
Zhang, Huoming
Celii, Mirko
Ocampo, Alejandro
Nuñez Delicado, Estrella
Mangiavacchi, Arianna
Aiese Cigliano, Riccardo
Horvath, Steve
Izpisua Belmonte, Juan Carlos
Orlando, Valerio
Venue: Science Translational Medicine
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2022-08-10
Volume: 14
Issue: 657
Pages: eabl6057-eabl6057
ISSN: 1946-6234 (ISSN-L)
1946-6242
DOI: 10.1126/scitranslmed.abl6057
OpenAlex: W4291020343
Cited by: 127
References: 69
Citations by year: 2026: 28 · 2025: 39 · 2024: 36 · 2023: 21 · 2022: 3
FWCI: 15.31
Type: journal article
Language: en
Open access: closed
Locations: Science Translational Medicine (publishedVersion)
PubMed (publishedVersion)
King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords: progeroid syndromes, premature aging, Hutchinson-Gilford progeria syndrome, SUV39H1, histone methyltransferase, antisense oligonucleotides, senescence-associated secretory phenotype, DNA methylation age, dermal fibroblasts, senolytic therapy, chromatin organization
MeSH terms: GADD45 Proteins, Animals, Antigens, Differentiation, Cockayne Syndrome, Heterochromatin, Histones, Humans, Lysine, Phenotype, Progeria, RNA, Telomere, Immediate-Early Proteins, Aging, Premature, Long Interspersed Nucleotide Elements, Tumor Suppressor Proteins, Mice

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

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