We thank CERCA Programme/Generalitat de Catalunya for institutional support. This work was supported by the Health Department PERIS-project no. SLT/002/16/00374 and AGAUR-projects no. 2017SGR1080 of the Catalan Government (Generalitat de Catalunya); Ministerio de Ciencia e Innovación (MCI), Agencia Estatal de Investigación (AEI) and European Regional Development Fund (ERDF) project no. RTI2018-094049-B-I00; the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant agreement No. 743168); the Varda and Boaz Dotan Research Center in Hemato-oncology affiliated to the Tel Aviv University; the Cellex Foundation; and "la Caixa" Banking Foundation (LCF/PR/GN18/51140001). ME is an ICREA Research Professor. ; Peer Reviewed ; "Article signat per 12 autors/es: Alberto Bueno-Costa, David Piñeyro, Carlos A. García-Prieto, Vanessa Ortiz-Barahona, Laura Martinez-Verbo, Natalie A. Webster, Byron Andrews, Nitzan Kol, Chen Avrahami, Sharon Moshitch-Moshkovitz, Gideon Rechavi & Manel Esteller" ; Postprint (published version)
Mouse has been extensively used as a model organism in many studies to characterize biological pathways and drug effects and to mimic human diseases. Similar DNA sequences between both species facilitate these types of experiments. However, much less is known about the mouse epigenome, particularly for DNA methylation. Progress in delivering mouse DNA methylomes has been slow due to the currently available time-consuming and expensive methodologies. Following the great acceptance of the human DNA methylation microarrays, we have herein validated a newly developed DNA methylation microarray (Infinium Mouse Methylation BeadChip) that interrogates 280,754 unique CpG sites within the mouse genome. The CpGs included in the platform cover CpG Islands, shores, shelves and open sea sequences, and loci surrounding transcription start sites and gene bodies. From a functional standpoint, mouse ENCODE representative DNase hypersensitivity sites (rDHSs) and candidate cis-Regulatory Elements (cCREs) are also included. Herein, we show that the profiled mouse DNA methylation microarray provides reliable values among technical replicates; matched results from fresh frozen versus formalin-fixed samples; detects hemimethylated X-chromosome and imprinted CpG sites; and is able to determine CpG methylation changes in mouse cell lines treated with a DNA demethylating agent or upon genetic disruption of a DNA methyltransferase. Most important, using unsupervised hierarchical clustering and t-SNE approaches, the platform is able to classify all types of normal mouse tissues and organs. These data underscore the great features of the assessed microarray to obtain comprehensive DNA methylation profiles of the mouse genome. ; We thank the CERCA Programme/Generalitat de Catalunya for institutional support. This work was supported by the Health Department PERIS-project no. SLT/002/16/00374 and AGAUR-project no. 2017SGR1080 of the Catalan Government (Generalitat de Catalunya); Ministerio de Ciencia e Innovación (MCI), Agencia Estatal de Investigación (AEI), and European Regional Development Fund (ERDF) project no. RTI2018-094049-B-I00 and PID2020-117284RB-I00; the Cellex Foundation; Marie Sklodowska-Curie Fellowship no. 895979 from the European Commission (BNV); and 'la Caixa' Banking Foundation (LCF/PR/GN18/51140001). ; Peer Reviewed ; Postprint (published version)
This work was supported by the Health Department PERIS-project no. SLT/002/16/00374 and AGAUR-projects no. 2017SGR1080, 2014SGR633, 2017SGR1033, and 2009SGR1315 of the Catalan Government (Generalitat de Catalunya); the Spanish Institute of Health Carlos III (ISCIII) project no. DTS16/00153, and CIBERONC CB16/12/00312 and CB16/12/00489; and Ministerio de Economía y Competitividad (MINECO) project nos. SAF2014-55000-R, BFU2014-57466-P, SAF2017-89673-R, SAF2017-86242-R, and SAF2015-70270-REDT cofinanced by the European Development Regional Fund, 'A way to achieve Europe' ERDF; the Cellex Foundation; and "la Caixa" Bank Foundation (LCF/PR/GN18/51140001). We thank Dr Thomas Graf for providing the transdifferentiation model.
Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease. ; This work was supported by a European Research Council (ERC) Advanced Grant under the European Community's Seventh Framework Program (FP7/2007-2013)/ERC Grant Agreement No. 268626—EPINORC project (to M. Esteller), the Ministerio de Economía y Competitividad (MINECO) under Grant No. SAF2014-55000-R (to M. Esteller) and the Instituto de Salud Carlos III (ISCIII), under the FIS PI16/01278 Project (to J. Seoane), the Integrated Project of Excellence no. PIE13/00022 (ONCOPROFILE) (to M. Esteller), CIBER 2016 CB16/12/00312 (CIBERONC) (to M. Esteller), co-financed by the European Development Regional Fund, 'A way to achieve Europe' ERDF, the AGAUR—Catalan Government (Project No. 2009SGR1315 and 2014SGR633) (to M. Esteller), the Cellex Foundation (to M. Esteller), Obra Social "La Caixa" (to M. Esteller), the CERCA Program and the Health and Science Departments of the Catalan Government (Generalitat de Catalunya) (to M. Esteller) and a grant from the National Health and Medical Research Council of Australia (APP1061551, to TP). M.W. Boudreau is a member of the NIH Chemistry-Biology Interface Training Program (T32-GM070421).
