TY - JOUR
T1 - LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes
AU - Valle, Francesco Della
AU - Reddy, Pradeep
AU - Yamamoto, Mako
AU - Liu, Peng
AU - Saera-Vila, Alfonso
AU - Bensaddek, Dalila
AU - Zhang, Huoming
AU - Martinez, Javier Prieto
AU - Abassi, Leila
AU - Celii, Mirko
AU - Ocampo, Alejandro
AU - Delicado, Estrella Nuñez
AU - Mangiavacchi, Arianna
AU - Cigliano, Riccardo Aiese
AU - Esteban, Concepcion Rodriguez
AU - Horvath, Steve
AU - Belmonte, Juan Carlos Izpisua
AU - Orlando, Valerio
N1 - Funding Information:
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).
Publisher Copyright:
© 2022 The Authors, some rights reserved.
PY - 2022/8/10
Y1 - 2022/8/10
N2 - 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 homo-log 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.
AB - 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 homo-log 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.
UR - http://www.scopus.com/inward/record.url?scp=85136339250&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.abl6057
DO - 10.1126/scitranslmed.abl6057
M3 - Article
C2 - 35947677
AN - SCOPUS:85136339250
SN - 1946-6234
VL - 14
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 657
M1 - eabl6057
ER -