Expression of DNA Methyltransferases Is Influenced by Growth Hormone in the Long-Living Ames Dwarf Mouse In Vivo and In Vitro

Armstrong, Vanessa; Rakoczy, Sharlene; Rojanathammanee, Lalida; Brown‐Borg, Holly M.

doi:10.1093/gerona/glt133

Cited by 38 publications

(32 citation statements)

References 62 publications

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“…For example, DNA methylation shows age‐specific linear changes in humpback whales ( Megaptera novaeangliae : Polanowski, Robbins, Chandler, & Jarman, 2014) but no changes in superb starlings (Rubenstein et al., 2016), possibly because these studies selected different candidate genes. In black grouse, we found a nonlinear (inverse u‐shaped) pattern of DNA methylation with age, as has similarly been reported in occasional human studies (for an example, see Armstrong, Rakoczy, Rojanathammanee, & Brown‐Borg, 2013). As our study focused primarily on the correlation between DNA methylation and sexual trait expression, such a pattern is to be expected.…”

Section: Discussionsupporting

confidence: 86%

Age‐ and quality‐dependent DNA methylation correlate with melanin‐based coloration in a wild bird

Soulsbury

Lipponen

Wood

et al. 2018

Ecology and Evolution

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Secondary sexual trait expression can be influenced by fixed individual factors (such as genetic quality) as well as by dynamic factors (such as age and environmentally induced gene expression) that may be associated with variation in condition or quality. In particular, melanin‐based traits are known to relate to condition and there is a well‐characterized genetic pathway underpinning their expression. However, the mechanisms linking variable trait expression to genetic quality remain unclear. One plausible mechanism is that genetic quality could influence trait expression via differential methylation and differential gene expression. We therefore conducted a pilot study examining DNA methylation at a candidate gene (agouti‐related neuropeptide: AgRP) in the black grouse Lyrurus tetrix. We specifically tested whether CpG methylation covaries with age and multilocus heterozygosity (a proxy of genetic quality) and from there whether the expression of a melanin‐based ornament (ultraviolet‐blue chroma) correlates with DNA methylation. Consistent with expectations, we found clear evidence for age‐ and heterozygosity‐specific patterns of DNA methylation, with two CpG sites showing the greatest DNA methylation in highly heterozygous males at their peak age of reproduction. Furthermore, DNA methylation at three CpG sites was significantly positively correlated with ultraviolet‐blue chroma. Ours is the first study to our knowledge to document age‐ and quality‐dependent variation in DNA methylation and to show that dynamic sexual trait expression across the lifespan of an organism is associated with patterns of DNA methylation. Although we cannot demonstrate causality, our work provides empirical support for a mechanism that could potentially link key individual factors to variation in sexual trait expression in a wild vertebrate.

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Section: Discussionsupporting

confidence: 86%

Age‐ and quality‐dependent DNA methylation correlate with melanin‐based coloration in a wild bird

Soulsbury

Lipponen

Wood

et al. 2018

Ecology and Evolution

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“…We selected liver for this study because our previous studies showed differences in liver in expression of DNA methyltransferases (DNMTs) between WT and Ames mice and young and old mice [45]. Also, a single cell type, the hepatocyte, comprises ~80% of liver mass, and the epigenome of mouse liver has been extensively characterised, thereby aiding downstream analysis of the methylome in the context of the wider epigenetic landscape.…”

Section: Resultsmentioning

confidence: 99%

Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions

et al. 2017

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BackgroundAge-associated epigenetic changes are implicated in aging. Notably, age-associated DNA methylation changes comprise a so-called aging “clock”, a robust biomarker of aging. However, while genetic, dietary and drug interventions can extend lifespan, their impact on the epigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylation changes at the whole-genome, single-nucleotide level in mouse liver and tested the impact of longevity-promoting interventions, specifically the Ames dwarf Prop1 df/df mutation, calorie restriction and rapamycin.ResultsIn wild-type mice fed an unsupplemented ad libitum diet, age-associated hypomethylation was enriched at super-enhancers in highly expressed genes critical for liver function. Genes harbouring hypomethylated enhancers were enriched for genes that change expression with age. Hypermethylation was enriched at CpG islands marked with bivalent activating and repressing histone modifications and resembled hypermethylation in liver cancer. Age-associated methylation changes are suppressed in Ames dwarf and calorie restricted mice and more selectively and less specifically in rapamycin treated mice.ConclusionsAge-associated hypo- and hypermethylation events occur at distinct regulatory features of the genome. Distinct longevity-promoting interventions, specifically genetic, dietary and drug interventions, suppress some age-associated methylation changes, consistent with the idea that these interventions exert their beneficial effects, in part, by modulation of the epigenome. This study is a foundation to understand the epigenetic contribution to healthy aging and longevity and the molecular basis of the DNA methylation clock.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1185-3) contains supplementary material, which is available to authorized users.

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“…We also observed methylation‐related pathways enriched in gene bodies gaining methylation. Interestingly, a previous study showed decreased expression of DNMT1 (Ray et al., 2006) in mouse T cells during aging; this is the main DNMT expressed in adulthood that maintains DNA methylation of adult dividing cells (Armstrong, Rakoczy, Rojanathammanee, & Brown‐Borg, 2014). These changes may contribute to misregulation of methylation machinery and a consequent entropy increase during aging.…”

Section: Discussionmentioning

confidence: 99%

Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction

2018

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SummaryAging is characterized by numerous molecular changes, such as accumulation of molecular damage and altered gene expression, many of which are linked to DNA methylation. Here, we characterize the blood DNA methylome across 16 age groups of mice and report numerous global, region‐ and site‐specific features, as well as the associated dynamics of methylation changes. Transition of the methylome throughout lifespan was not uniform, with many sites showing accelerated changes in late life. The associated genes and promoters were enriched for aging‐related pathways, pointing to a fundamental link between DNA methylation and control of the aging process. Calorie restriction both shifted the overall methylation pattern and was accompanied by its gradual age‐related remodeling, the latter contributing to the lifespan‐extending effect. With age, both highly and poorly methylated sites trended toward intermediate levels, and aging was accompanied by an accelerated increase in entropy, consistent with damage accumulation. However, the entropy effects differed for the sites that increased, decreased and did not change methylation with age. Many sites trailed behind, whereas some followed or even exceeded the entropy trajectory and altered the developmental DNA methylation pattern. The patterns we observed in certain genomic regions were conserved between humans and mice, suggesting common principles of functional DNA methylome remodeling and its critical role in aging. The highly resolved DNA methylome remodeling provides an excellent model for understanding systemic changes that characterize the aging process.

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Expression of DNA Methyltransferases Is Influenced by Growth Hormone in the Long-Living Ames Dwarf Mouse In Vivo and In Vitro

Cited by 38 publications

References 62 publications

Age‐ and quality‐dependent DNA methylation correlate with melanin‐based coloration in a wild bird

Age‐ and quality‐dependent DNA methylation correlate with melanin‐based coloration in a wild bird

Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions

Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction

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