DNA methylation networks underlying mammalian traits

Abstract

Using DNA methylation profiles ( n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.

Aging and cancer

“…Throughout the aging process, such epigenetic changes are progressively lost, increasing the noise in the system, and contributing to a progressive loss of cellular identities that menaces the functional integrity of complex tissues and potentially enhances the risk of carcinogenesis coupled to an increase in tumor heterogeneity and phenotypic plasticity [ 42 ]. The most common (but still imperfect) technology to measure epigenetic shifts consists in bisulfite pyrosequencing to detect DNA methylation patterns that can be bioinformatically deconvoluted as “biological clocks” and be associated to the risks of developing specific diseases [ 43 ].…”

MammalMethylClock R package: software for DNA Methylation-Based Epigenetic Clocks in Mammals

“…The vast majority of our epigenetic clocks are based on CpGs that map to the respective genome. Although our R package doesn’t directly contain genome annotation files, CpG genome annotations for many hundreds of species (including non-mammalian species) are available on the Mammalian Methylation Consortium’s GitHub page 12,13 (Horvath, S., Lu, A.T., Li, C.Z., Haghani, A., Arneson, A., Ernest, J. & Mammalian, M.C.…”

“…These spanned 59 tissue types and were sourced from 185 mammalian species representing 19 taxonomic orders. Remarkably, the age range of these samples extends from prenatal stages right up to a venerable 139 years, as seen in the bowhead whale (Balaena mysticetus) 12,13 . We published numerous epigenetic clocks tailored to specific species and tissue types 14–38 .…”

MammalMethylClock R package: software for DNA methylation-based epigenetic clocks in mammals

“…The Mammalian Methylation Consortium used the mammalian methylation array, which measures DNA methylation levels in 37 492 CpGs, including those flanking DNA sequences that are highly conserved across mammals ( Arneson et al 2022 ). The consortium successfully profiled over 15 000 samples from 348 mammalian species ( Haghani et al 2023 , Lu et al 2023 ) and published many epigenetic clocks tailored to specific species and tissue types [see the software’s GitHub page ( https://github.com/jazoller96/mammalian-methyl-clocks/tree/main ) or the “getClockDatabase()” function for a list of references for all of the clocks included in this software]. In the following, we present the R software tools and the accompanying statistical techniques pivotal for the development, assessment, and application of these epigenetic clocks.…”