Epigenetics, DNA damage, and aging.

Over the course of a human lifespan, genome integrity erodes, leading to an increased abundance of several types of chromatin changes. The abundance of DNA lesions (chemical perturbations to nucleotides) increases with age, as does the number of genomic mutations and transcriptional disruptions caused by replication or transcription of those lesions, respectively. At the epigenetic level, precise DNA methylation patterns degrade, likely causing increasingly stochastic variations in gene expression. Similarly, the tight regulation of histone modifications begins to unravel. The genomic instability caused by these mechanisms allows transposon element reactivation and remobilization, further mutations, gene dysregulation, and cytoplasmic chromatin fragments. This cumulative genomic instability promotes cell signaling events that drive cell fate decisions and extracellular communications known to disrupt tissue homeostasis and regeneration. In this Review, we focus on age-related epigenetic changes and their interactions with age-related genomic changes that instigate these events.

Effect of supplementing lactation and nursery pig diets with capsaicin on growth performance and gene expression of nursery pigs.

The objective of this study was to determine the effects of supplementing capsaicin in diets for lactating sows and their offspring on the growth performance and gene expression of pigs postweaning. Twenty-eight multiparous sows were fed corn-soybean meal-based diets without (n = 14) and with (n = 14) capsaicin (2.5 mg/kg) during a 19-d lactation period. Litters from these sows (n = 288 pigs) were weaned and assigned to 36 blocks (pens) based on maternal dietary treatment and initial body weight (BW) to provide 8 pigs/pen. Blocks were assigned randomly to one of two nursery dietary treatments (control or capsaicin supplemented diets) in a 2 × 2 factorial arrangement of treatments to provide nine replications per treatment combination. A three-phase nursery feeding program was used and consisted of feeding phase 1 (weaning to d 7), phase 2 (d 8-21), and phase 3 (d 22-38) diets postweaning, without and with 1.0, 1.3, and 1.6 mg capsaicin/kg of diet, respectively. Data were analyzed using a mixed model with the effect of nursery dietary treatment nested within sow lactation treatment, the effect of time with repeated measures, and interactions between treatments and wk postweaning. On d 38 postweaning, blood samples were collected from one pig in each pen (n = 36) with BW closest to the pen average for RNA sequencing and gene expression analysis. There were no effects of feeding capsaicin diets to lactating sows and/or their weaned offspring on BW, average daily gain, or average daily feed intake of pigs during the 35-d nursery period. However, pigs weaned from sows fed capsaicin during lactation and continuing to be fed capsaicin diets during the nursery period tended (P = 0.09) to have greater gain:feed (G:F) than pigs fed the other dietary treatments. Furthermore, there was an interaction (P < 0.01) for G:F for dietary treatment and week postweaning, where the magnitude of improvement was greater during the first week postweaning than subsequent wks. There were a limited number of differentially expressed genes among dietary treatment combinations but the greatest number occurred in offspring from sows that were fed capsaicin during lactation. In conclusion, the combination of feeding capsaicin to sows during lactation and to their offspring after weaning appears to improve gain efficiency for the first wk postweaning and may alter gene expression to a greater extent than when capsaicin is supplemented only in the nursery diets.

Early-life social experience affects offspring DNA methylation and later life stress phenotype.

Studies in rodents and captive primates suggest that the early-life social environment affects future phenotype, potentially through alterations to DNA methylation. Little is known of these associations in wild animals. In a wild population of spotted hyenas, we test the hypothesis that maternal care during the first year of life and social connectedness during two periods of early development leads to differences in DNA methylation and fecal glucocorticoid metabolites (fGCMs) later in life. Here we report that although maternal care and social connectedness during the den-dependent life stage are not associated with fGCMs, greater social connectedness during the subadult den-independent life stage is associated with lower adult fGCMs. Additionally, more maternal care and social connectedness after den independence correspond with higher global (%CCGG) DNA methylation. We also note differential DNA methylation near 5 genes involved in inflammation, immune response, and aging that may link maternal care with stress phenotype.

Early life social and ecological determinants of global DNA methylation in wild spotted hyenas.

Environmental factors early in life can have lasting influence on the development and phenotypes of animals, but the underlying molecular modifications remain poorly understood. We examined cross-sectional associations among early life socioecological factors and global DNA methylation in 293 wild spotted hyenas (Crocuta crocuta) in the Masai Mara National Reserve, Kenya, grouped according to three age classes (cub, subadult and adult). Explanatory variables of interest included annual maternal rank based on outcomes of dyadic agonistic interactions, litter size, wild ungulate prey density and anthropogenic disturbance in the year each hyena was born based on counts of illegal livestock in the Reserve. The dependent variable of interest was global DNA methylation, assessed via the LUminometric Methylation Assay, which provides a percentage methylation value calculated at CCGG sites across the genome. Among cubs, we observed approximately 2.75% higher CCGG methylation in offspring born to high- than low-ranking mothers. Among cubs and subadults, higher anthropogenic disturbance corresponded with greater %CCGG methylation. In both cubs and adults, we found an inverse association between prey density measured before a hyena was 3 months old and %CCGG methylation. Our results suggest that maternal rank, anthropogenic disturbance and prey availability early in life are associated with later life global DNA methylation. Future studies are required to understand the extent to which these DNA methylation patterns relate to adult phenotypes and fitness outcomes.

Perinatal Lead (Pb) Exposure and Cortical Neuron-Specific DNA Methylation in Male Mice.

: Lead (Pb) exposure is associated with a wide range of neurological deficits. Environmental exposures may impact epigenetic changes, such as DNA methylation, and can affect neurodevelopmental outcomes over the life-course. Mating mice were obtained from a genetically invariant C57BL/6J background agouti viable yellow Avy strain. Virgin dams (a/a) were randomly assigned 0 ppm (control), 2.1 ppm (low), or 32 ppm (high) Pb-acetate water two weeks prior to mating with male mice (Avy/a), and this continued through weaning. At age 10 months, cortex neuronal nuclei were separated with NeuN⁺ antibodies in male mice to investigate neuron-specific genome-wide promoter DNA methylation using the Roche NimbleGen Mouse 3x720K CpG Island Promoter Array in nine pooled samples (three per dose). Several probes reached p-value < 10-5 , all of which were hypomethylated: 12 for high Pb (minimum false discovery rate (FDR) = 0.16, largest intensity ratio difference = -2.1) and 7 for low Pb (minimum FDR = 0.56, largest intensity ratio difference = -2.2). Consistent with previous results in bulk tissue, we observed a weak association between early-life exposure to Pb and DNA hypomethylation, with some affected genes related to neurodevelopment or cognitive function. Although these analyses were limited to males, data indicate that non-dividing cells such as neurons can be carriers of long-term epigenetic changes induced in development.

Epigenetics and the maintenance of developmental plasticity: extending the signalling theory framework.

Developmental plasticity, a phenomenon of importance in both evolutionary biology and human studies of the developmental origins of health and disease (DOHaD), enables organisms to respond to their environment based on previous experience without changes to the underlying nucleotide sequence. Although such phenotypic responses should theoretically improve an organism's fitness and performance in its future environment, this is not always the case. Herein, we first discuss epigenetics as an adaptive mechanism of developmental plasticity and use signaling theory to provide an evolutionary context for DOHaD phenomena within a generation. Next, we utilize signalling theory to identify determinants of adaptive developmental plasticity, detect sources of random variability - also known as process errors that affect maintenance of an epigenetic signal (DNA methylation) over time, and discuss implications of these errors for an organism's health and fitness. Finally, we apply life-course epidemiology conceptual models to inform study design and analytical strategies that are capable of parsing out the potential effects of process errors in the relationships among an organism's early environment, DNA methylation, and phenotype in a future environment. Ultimately, we hope to foster cross-talk and interdisciplinary collaboration between evolutionary biology and DOHaD epidemiology, which have historically remained separate despite a shared interest in developmental plasticity.

YY1's DNA-binding motifs in mammalian olfactory receptor genes.

BACKGROUND: YY1 is an epigenetic regulator for a large number of mammalian genes. While performing genome-wide YY1 binding motif searches, we discovered that the olfactory receptor (OLFR) genes have an unusual cluster of YY1 binding sites within their coding regions. The statistical significance of this observation was further analyzed. RESULTS: About 45% of the olfactory genes in the mouse have a range of 4-8 YY1 binding sites within their respective 1 kb coding regions. Statistical analyses indicate that this enrichment of YY1 motifs has likely been driven by unknown selection pressures at the DNA level, but not serendipitously by some peptides enriched within the OLFR genes. Similar patterns are also detected in the OLFR genes of all mammals analyzed, but not in the OLFR genes of the fish lineage, suggesting a mammal-specific phenomenon. CONCLUSION: YY1, or YY1-related transcription factors, may help regulate olfactory receptor genes. Furthermore, the protein-coding regions of vertebrate genes can contain cis-regulatory elements for transcription factor binding as well as codons.