Conservation of aging and cancer epigenetic signatures across human and mouse
Aging and cancer are two interrelated processes, with aging being a major risk factor for the development of cancer. Parallel epigenetic alterations have been described for both, although differences, especially within the DNA hypomethylation scenario, have also been recently reported. Although many of these observations arise from the use of mouse models, there is a lack of systematic comparisons of human and mouse epigenetic patterns in the context of disease. However, such comparisons are significant as they allow to establish the extent to which some of the observed similarities or differences arise from pre-existing species-specific epigenetic traits. Here, we have used reduced representation bisulfite sequencing to profile the brain methylomes of young and old, tumoral and nontumoral brain samples from human and mouse. We first characterized the baseline epigenomic patterns of the species and subsequently focused on the DNA methylation alterations associated with cancer and aging. Next, we described the functional genomic and epigenomic context associated with the alterations, and finally, we integrated our data to study interspecies DNA methylation levels at orthologous CpG sites. Globally, we found considerable differences between the characteristics of DNA methylation alterations in cancer and aging in both species. Moreover, we describe robust evidence for the conservation of the specific cancer and aging epigenomic signatures in human and mouse. Our observations point toward the preservation of the functional consequences of these alterations at multiple levels of genomic regulation. Finally, our analyses reveal a role for the genomic context in explaining disease- and species-specific epigenetic traits. ; This work was supported by the Spanish Association Against Cancer (PROYE18061FERN to M.F.F.), the Asturias Government (PCTI) cofunding 2018-2022/FEDER (IDI/2018/146 to M.F.F.), Fundación General CSIC (0348_CIE_6_E to M.F.F.), and the Health Institute Carlos III (Plan Nacional de I + D+I) cofunding FEDER (PI15/00892 and PI18/01527 to M.F.F and A.F.F.). They also acknowledge support from the Ramón Areces Foundation (CIVP18A3891 to P.J.F.M.), the AECC (SIRTBIO to P.J.F.M.), the MICINN (SAF2017-85766-R to P.J.F.M.), a Ramón y Cajal fellowship (MICINN, RYC-2017-22335 to P.J.F.M.), and the European Commission ATTRACT project (777222 to A.P.C.). J.R.T. is supported by a Juan de la Cierva fellowship from the Spanish Ministry of Science and Innovation (FJCI-2015-26965). R.F.P. and P.S.O. are supported by the Severo Ochoa program (BP17-114 and BP17-165, respectively). R.G.U. is supported by the Centro de Investigación Biomédica en Red de Enfermedades Raras (Health Institute Carlos III). L.V. was supported by the UAB Predoctoral training programme (PIF predoctoral fellowships). They also acknowledge support from the IMDEA Food Institute and IUOPA-ISPA-FINBA (the IUOPA is supported by the Obra Social Cajastur-Liberbank, Spain). ; Peer reviewed