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; Belmonte, Juan Carlos Izpisua; Orlando, Valerio

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.

Citation

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. (2022). LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes. Science Translational Medicine, 14(657). https://doi.org/10.1126/scitranslmed.abl6057

Acknowledgements

RNA-seq library preparation and Illumina sequencing were performed by Institute of Applied Genomics (IGA) service by V. Vendramin. L1 ASO–Cy5 injection and IVIS imaging were performed by Charles River U.K. Inducible GFP-Progerin and GFP-LaminA human dermal fibroblasts were a gift from T. Misteli (Center for Cancer Research, NIH, Bethesda). pTNC7 L1spa plasmid was a gift from E. Heard (Institute Curie, Paris and European Molecular Biology Laboratory, Heidelberg). The work was supported by KAUST BAS/1/01-01, KAUST Competitive Research Grant Program, and KAUST Smart Health Initiative to V.O. Work in the laboratory of J.C.I.B. at the Salk Institute was supported by The Moxie Foundation and Universidad Católica San Antonio de Murcia (UCAM).