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Epigenomic Signature of the Progeroid Cockayne Syndrome Exposes Distinct and Common Features with Physiological Ageing

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Epigenomic Signature of the Progeroid Cockayne Syndrome Exposes Distinct and Common Features with Physiological Ageing bioRxiv preprint doi: https://doi.org/10.1101/2021.05.23.445308; this version posted May 24, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Epigenomic signature of the progeroid Cockayne syndrome exposes distinct and common features with physiological ageing Clément Crochemore1,2, Claudia Chica3, Paolo Garagnani4,5,6, Giovanna Lattanzi6,7, Steve Horvath8, 9 10 11☨ 1☨* Alain Sarasin , Claudio Franceschi , Maria Giulia Bacalini , and Miria Ricchetti ☨co-last authors 1Institut Pasteur, Team Stability of Nuclear and Mitochondrial DNA, Stem Cells and Development, UMR 3738 CNRS, 25-28 rue du Dr. Roux, 75015 Paris, France 2Sup’Biotech, 66 rue Guy Moquet, 94800 Villejuif, France 3Institut Pasteur – Bioinformatics and Biostatistics Hub – Department of Computational Biology, 25-28 rue du Dr. Roux, 75015, Paris, France 4Department of Laboratory Medicine, Clinical Chemistry, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden 5Applied Biomedical Research Center (CRBA), Policlinico S.Orsola-Malpighi Polyclinic, Bologna, Italy 6CNR Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, Unit of Bologna, Bologna, Italy 7IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy 8Department of Human Genetics, David Geffen School of Medicine, Department of Biostatistics Fielding School of Public Health, University of California, Los Angeles, USA 9Laboratory of Genetic Stability and Oncogenesis, Institut de cancérologie Gustave Roussy, and University Paris-Sud, 114 rue Edouard Vaillant, 94805 Villejuif, France 10Institute of Information Technologies, Mathematics and Mechanics, Lobachevsky University, Nizhniy Novgorod, Russia 11IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy *Corresponding authors: Miria Ricchetti ([email protected]) and Maria Giulia Bacalini ([email protected]) Keywords: Cockayne syndrome, UV-sensitivity syndrome, DNA methylation, progeroid diseases, ageing bioRxiv preprint doi: https://doi.org/10.1101/2021.05.23.445308; this version posted May 24, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Cockayne syndrome (CS) and UV-sensitivity syndrome (UVSS) are rare genetic disorders caused by mutation of the DNA repair and chromatin remodelling proteins CSA or CSB, but only CS patients display a progeroid and neurodegenerative phenotype. As epigenetic modifications constitute a well-established hallmark of ageing, we characterized genome-wide DNA methylation (DNAm) of fibroblasts from CS versus UVSS patients and healthy donors. The analysis of differentially methylated positions and regions revealed a CS-specific epigenetic signature, enriched in developmental transcription factors, transmembrane transporters, and cell adhesion factors. The CS-specific signature compared to DNAm changes in other progeroid diseases and regular ageing, identifyied commonalities and differences in epigenetic remodelling. CS shares DNAm changes with normal ageing more than other progeroid diseases do, and according to the methylation clock CS samples show up to 13-fold accelerated ageing. Thus, CS is characterized by a specific epigenomic signature that partially overlaps with and exacerbates DNAm changes occurring in physiological aging. Our results unveil new genes and pathways that are potentially relevant for the progeroid/degenerative CS phenotype. Introduction In several rare genetic disorders ageing is greatly accelerated1, but the molecular defects leading to precocious ageing are still unknown. Progeroid syndromes are genetically, biochemically, and clinically heterogeneous. While Hutchinson–Gilford progeria syndrome (HGPS) is due to a defective nuclear lamina as a consequence of mutations in LMNA gene, Cockayne syndrome (CS) and Werner syndrome (WS) result from mutation in multifunctional proteins best known for their role in DNA repair. It is not yet known which genes on chromosome 21 contribute to the progeroid phenotype of trisomy 21 also known as Down syndrome (DS). The extent and combination of ageing-related defects2 are specific to each progeroid syndrome. Since not all alterations observed during regular ageing are clinically recapitulated, these conditions are often referred to as segmental progeroid syndromes3. Here we focus on CS which is a devastating multisystemic disease characterized by neurodevelopmental defects, precocious ageing, and in most cases cutaneous photosensitivity. It is a progressive disorder with most symptoms appearing relatively early in life and worsening with time4. 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.23.445308; this version posted May 24, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Multiple degrees of severity have been described, including a prenatal-onset form known as cerebro- oculo-facioskeletal (COFS) syndrome, an early-onset severe form (CS type II, average age of death 5- 6 years), a classical or moderate form (CS type I, mean life expectancy around 16 years) and a mild or late-onset form (CS type III)5. CS is due to mutations in either CSB or CSA genes (approximately 70:30 ratio)5,6, which code repair factors of UV-induced DNA damage through the transcription-coupled nucleotide excision repair (TC-NER) pathway7. CS defects, including the precocious ageing phenotype, have been essentially ascribed to impaired DNA repair. Nevertheless, mutations in CSB or CSA are also responsible for an independent syndrome, the UV-sensitive syndrome (UVSS) that is characterized by severe photosensitivity but no sign of premature ageing8,9. About 8 cases of UVSS, which display a similar phenotype, are known worldwide and some of which are due to mutations in UVSSA, a protein that acts in TC-NER in concert with CSA and CSB10,11. These case reports de facto uncouple the DNA repair defect from precocious ageing and suggest that impairment of other functions of multifunctional CSA and CSB proteins are responsible for progeroid defects. Indeed, CSA and CSB are also transcription factors12, are implicated in chromatin remodelling13,14, and have been detected in mitochondria where they act in repairing oxidative damage15 and promoting transcription16 of mitochondrial DNA. Additionally, we showed that in CS (but not UVSS) cells the CSA/CSB impairment results in overexpression of the HTRA3 protease leading to degradation of the mitochondrial DNA polymerase POLG1, and consequent mitochondrial dysfunction17. CSA and CSB mutations represent therefore an exceptional case for disentangling downstream genes and pathways involved in dramatically different phenotypes, since their impairment results (CS) or not (UVSS) in accelerated ageing. We recently associated the CS-specific HTRA3/POLG1/mitochondrial alterations with replicative senescence in normal cells, and identified CSB depletion as an early trigger of this process, mechanistically linking progeroid defects with a major ageing-related process18. Different molecular hallmarks of ageing (e.g. epigenetic alterations, senescence, and mitochondrial dysfunction) have been identified19. DNA methylation, an epigenetic mechanism corresponding to the addition of a methyl group in the fifth position of a cytosine could contribute to the ageing process since it is associated with important changes in gene expression20. DNA methylation globally decreases with ageing, largely as a consequence of demethylation of repetitive retroelements (LINEs, Alu sequences), driving genomic instability21. In recent years, epigenome-wide association 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.23.445308; this version posted May 24, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. studies (EWAS) performed in ageing contexts demonstrated that hypo-/hyper-methylation of specific sets of CpGs can be used to build epigenetic clocks, which are predictive of chronological age or mortality risk (i.e, the phenotypic age or GrimAge of an individual)22-24. Important alterations of the DNA methylation profile were described in progeroid WS-, HGPS-, and DS-derived cells compared to healthy controls25-28, and were associated with increased epigenetic age25,29,30. We performed genome-wide analysis of the methylome of CS and UVSS patients, with the aim of discriminating CS-specific ageing-related DNA methylation changes by filtering out the UVSS condition (mutated but non-progeroid). This analysis identified genes enriched in three major categories, many of which have not been previously associated with ageing. We also demonstrated a dramatic increase of the epigenetic age of CS fibroblasts, and comparison with available datasets revealed a CS epigenetic signature closer to physiological ageing than HGPS, WS or DS, underscoring CS as a relevant model of accelerated ageing. Results Genome-wide DNA methylation of fibroblasts from CS, UVSS and healthy subjects We analysed genome-wide DNA methylation in dermal fibroblasts isolated from 7 CS patients, 2 UVSS patients and 3 healthy subjects, with no siblings, and at similar passage number. An overview of the study design is reported in Fig S1. Samples were processed using the Infinium HumanMethylation450 BeadChip or
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