Conservation of Aging and Cancer Epigenetic Signatures across Human and Mouse

Abstract

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. While 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 non-tumoral 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 towards 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.

The Role of SOX Transcription Factors in Ageing and Age-Related Diseases

“…One of the main epigenetic phenomena shared between aged mouse and human was ageing-associated DNA methylation changes found at TF-binding sites. Interestingly, DNA methylation alteration in both species was commonly found in HMG domains of several SOX TFs [21].…”

Aging and cancer epigenetics: Where do the paths fork?

“…This has been especially the case with research involving mouse models of aging, which have failed to report global DNA hypomethylation in this process, across multiple tissues (Cole et al, 2017 ; Hadad et al, 2019 ; Hahn et al, 2017 ; Hernando‐Herraez et al, 2019 ; Masser et al, 2017 ; Sun et al, 2014 ). These observations have prompted systematic studies to be undertaken that seek to accurately characterize the similitudes and differences between aging‐ and cancer‐associated epigenetic alterations, often revealing clear differences between aging, cancer, and senescence (Pérez et al, 2018 ; Xie et al, 2018 ), some of which have been detectable across human and mouse (Pérez et al, 2021 ). There is therefore a need to clarify, within the epigenetic context, the functional relationships between the two processes.…”