title: Conserved effect of aging on DNA methylation and association with EZH2 polycomb protein in mice and humans.
abstract: In humans, DNA methylation at specific CpG sites can be used to estimate the 'epigenetic clock', a biomarker of aging and health. The mechanisms that regulate the aging epigenome and level of conservation are not entirely clear. We performed affinity-based enrichment with methyl-CpG binding domain protein followed by high-throughput sequencing (MBD-seq) to assay DNA methylation in mouse samples. Consistent with previous reports, aging is associated with increase in methylation at CpG islands that likely overlap regulatory regions of genes that have been implicated in cancers (e.g., C1ql3, Srd5a2 and Ptk7). The differentially methylated regions in mice have high sequence conservation in humans and the pattern of methylation is also largely conserved between the two species. Based on human ENCODE data, these sites are targeted by polycomb proteins, including EZH2. Chromatin immunoprecipitation confirmed that these regions interact with EZH2 in mice as well, and there may be reduction in EZH2 occupancy with age at C1ql3. This adds to the growing evidence that EZH2 is part of the protein machinery that shapes the aging epigenome. The conservation in both sequence and methylation patterns of the age-dependent CpGs indicate that the epigenetic clock is a fundamental feature of aging in mammals.
authors.affiliation: Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA. Electronic address: kmozhui@uthsc.edu.
authors.forename: Khyobeni
authors.initials: K
authors.lastname: Mozhui
authors.affiliation: Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Ashutosh K
authors.initials: AK
authors.lastname: Pandey
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018899:CpG Islands / Q000502:physiology*; D019175:DNA Methylation / Q000502:physiology*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human; C548470:Srd5a2 protein, mouse; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; C096905:PTK7 protein, human; C486452:Ptk7 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases
keywords: DNA methylation; EZH2; Epigenetics; MBD sequencing; Polycomb repressive complex