Emma S Garratt

• PhD
• PostDoc Position at University of Southampton

Background An adverse early‐life environment is associated with impaired muscle mass and function in later life, with epigenetic processes proposed as mediators. The aim of this study was to investigate whether early‐life exposures were associated with altered patterns of DNA methylation in cultured myoblasts isolated from community‐dwelling older...

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1,2,3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonell...

Small noncoding RNAs (sncRNAs) are implicated in age‐associated pathologies, including sarcopenia and insulin resistance (IR). As potential circulating biomarkers, most studies have focussed on microRNAs (miRNAs), one class of sncRNA. This study characterized the wider circulating sncRNA transcriptome of older individuals and associations with sarc...

Background While ageing is associated with increased insulin resistance (IR), the molecular mechanisms underlying increased IR in the muscle, the primary organ for glucose clearance, have yet to be elucidated in older individuals. As epigenetic processes are suggested to contribute to the development of ageing-associated diseases, we investigated w...

Background Amongst healthy older people, a number of correlates of impaired skeletal muscle mass and function have been defined. Although the prevalence of obesity is increasing markedly in this age group, information is sparse about the particular impacts of obesity on ageing skeletal muscle or the molecular mechanisms that underlie this and assoc...

Background Sarcopenia is the age-related loss of muscle mass, strength, and function. Epigenetic processes such as DNA methylation, which integrate both genetic and environmental exposures, have been suggested to contribute to the development of sarcopenia. This study aimed to determine whether differences in the muscle methylome are associated wit...

Background Despite increasing knowledge of the pathogenesis of muscle ageing, the molecular mechanisms are poorly understood. Based on an expression analysis of muscle biopsies from older Caucasian men, we undertook an in-depth analysis of the expression of the long non-coding RNA, H19, to identify molecular mechanisms that may contribute to the lo...

Many epidemiological studies have linked low birthweight to an increased risk of non-communicable diseases (NCDs) in later life, with epigenetic proceseses suggested as an underlying mechanism. Here, we sought to identify neonatal methylation changes associated with birthweight, at both the individual CpG and genomic regional level, and whether the...

Background Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks’ gestation and DNA methylation in neonat...

The causes of impaired skeletal muscle mass and strength during aging are well-studied in healthy populations. Less is known on pathological age-related muscle wasting and weakness termed sarcopenia, which directly impacts physical autonomy and survival. Here, we compare genome-wide transcriptional changes of sarcopenia versus age-matched controls...

We have previously demonstrated inverse associations between maternal 25(OH)‐vitamin D status and perinatal DNA methylation at the retinoid‐X‐receptor‐alpha (RXRA) locus and between RXRA methylation and offspring bone mass. We therefore used an existing randomised trial to test the hypothesis that maternal gestational vitamin D supplementation woul...

Background: There is now increasing evidence that asthma and atopy originate in part in utero, with disease risk being associated with the altered epigenetic regulation of genes. Objective and methods: To determine the relationship between variations in DNA methylation at birth and the development of allergic disease, we examined the methylation...

Supplementary material

Poor intrauterine and childhood growth has been linked with the risk of osteoporosis in later life, a relationship which may in part be mediated through altered epigenetic regulation of genes. We previously identified a region within the promoter of the long non-coding RNA ANRIL encoded by the CDKN2A locus, at which differential DNA methylation at...

Experimental studies show a substantial contribution of early life environment to obesity risk through epigenetic processes. We examined inter-individual DNA methylation differences in human birth tissues associated with child's adiposity. We identified a novel association between the level of CpG methylation at birth within the promoter of the lon...

Early life environments induce long-term changes in neurocognitive development and behaviour. In animal models, early environmental cues affect neuropsychological phenotypes via epigenetic processes but as yet there is little direct evidence for such mechanisms in humans. Method: We examined the relation between DNA methylation at birth and child...

Childhood obesity is a major public health issue. Here we investigated whether differential DNA methylation was associated with childhood obesity. We studied DNA methylation profiles in whole blood from 78 obese children (mean BMI Z-score: 2.6) and 71 age- and sex-matched controls (mean BMI Z-score: 0.1). DNA samples from obese and control groups w...

Early life environments induce long-term changes in neurocognitive development and behaviour. In animal models, early environmental cues affect neuropsychological phenotypes via epigenetic processes but, as yet, there is little direct evidence for such mechanisms in humans. We examined the relation between DNA methylation at birth and child neurops...

Maternal vitamin D deficiency has been associated with reduced offspring bone mineral accrual. Retinoid-X Receptor-alpha (RXRA) is an essential cofactor in the action of 1,25(OH)2 -vitamin D, and RXRA methylation in umbilical cord DNA has been associated with later offspring adiposity. We tested the hypothesis that RXRA methylation in umbilical cor...

The genes encoding nuclear receptors comprise multiple 5'untranslated exons, which give rise to several transcripts encoding the same protein, allowing tissue-specific regulation of expression. Both human and mouse peroxisome proliferator activated receptor (PPAR) α genes have multiple promoters, although their function is unknown. Here we have cha...

Our previous work has shown associations between childhood adiposity and perinatal methylation status of several genes in umbilical cord tissue, including endothelial nitric oxide synthase (eNOS). There is increasing evidence that eNOS is important in bone metabolism; we therefore related the methylation status of the eNOS gene promoter in stored u...

Objective: fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans. Research design and methods: using Sequenom MassARRAY we measur...

Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans. Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5'...

Feeding pregnant rats a protein-restricted (PR) diet induces altered expression of candidate genes in the liver of the adult offspring, which can be prevented by supplementation of the PR diet with folic acid (PRF). We investigated the effect of maternal nutrition during pregnancy on the liver transcriptome in their adult male offspring. Pregnant r...

Effect of maternal dietary restriction during pregnancy in rats on PPARα-regulated genes in the heart of the male offspring - Volume 69 Issue OCE1 - J. Slater-Jefferies, E. Phillips, K. Lillycrop, P. Townsend, M. Hanson, G. Burdge

Prenatal nutritional constraint is associated with increased risk of metabolic dysregulation in adulthood contingent on adult diet. In rats, folic acid supplementation of a protein-restricted (PR) diet during pregnancy prevents altered phenotype and epigenotype in the offspring induced by the PR diet. We hypothesized that increasing folic acid inta...

Induction of an altered phenotype by prenatal under-nutrition involves changes in the epigenetic regulation of specific genes. We investigated the effect of feeding pregnant rats a protein-restricted (PR) diet with different amounts of folic acid on the methylation of individual CpG dinucleotides in the hepatic PPAR alpha promoter in juvenile offsp...

Administration of leptin to neonatal offspring of rats exposed to 70 % global undernutrition (UN group) during pregnancy prevents increased weight gain when fed a high-fat diet after weaning compared with the offspring of pregnant dams fed ad libitum (AL group) (1). Administration of leptin to adult rats induces a transient increase in PPARa mRNA e...

Reduced PPARa expression, and hence impaired fatty acid b-oxidation and deposition of TAG in the myocardium, is associated with cardiomyopathy (1). Restricting dietary protein intake of pregnant rats induces altered cardiovascular function in the offspring (2). The present study has investigated the effect of feeding a protein-restricted (PR) diet...

Developmental plasticity in response to environmental cues can take the form of polyphenism, as for the discrete morphs of some insects, or of an apparently continuous spectrum of phenotype, as for most mammalian traits. The metabolic phenotype of adult rats, including the propensity to obesity, hyperinsulinemia, and hyperphagia, shows plasticity i...

Epidemiological studies and experimental models show that maternal nutritional constraint during pregnancy alters the metabolic phenotype of the offspring and that this can be passed to subsequent generations. In the rat, induction of an altered metabolic phenotype in the liver of the F1 generation by feeding a protein-restricted diet (PRD) during...

Induction of an altered metabolic phenotype in the offspring of rats fed a protein-restricted (PR) diet during pregnancy involves hypomethylation and increased expression of the hepatic glucocorticoid receptor (GR) and PPARa promoters. To determine the mechanism responsible for promoter hypomethylation we investigated the effect of feeding a PR die...

Background: There is evidence in humans and experimental animals for non-genomic transmission of induced phenotypes between generations. Induction of an altered phenotype in the F1 generation by feeding a protein-restricted (PR) diet to pregnant rats involves altered epigenetic regulation of specific genes. We investigated whether altered epigeneti...

In healthy individuals, glucose and fatty acids are substrates for ATP generation in the heart. There is emerging evidence from patients with type 2 diabetes mellitus that preferential use of fatty acid b-oxidation for energy production may be linked to cardiomyopathy (Fink, 2004). PPARa activity is important for regulating fatty acid b-oxidation i...

Environmental constraints during early life result in phenotypic changes that can be associated with increased disease risk in later life. This suggests persistent alteration of gene transcription. DNA methylation, which is largely established in utero, provides a causal mechanism by which unbalanced prenatal nutrition results in such altered gene...

Nramp1 (murine natural resistance-associated macrophage protein 1 gene)/Slc11a1 (solute carrier family 11 member a1 gene) encodes a bivalent-metal/iron transporter that is expressed within late endosomes/lysosomes of macrophages. A functionally null Nramp1 allele that exhibits impaired bivalent cation transport enables excessive growth of intracell...

The effect of protein consumption during pregnancy on peroxisomal proliferator-activated receptor (PPAR) expression and plasma lipid concentrations in the offspring were determined in the rat. Rats were fed isocaloric diets containing either 18% (w/w) (control) or 9% (w/w) casein throughout pregnancy, and chow during lactation. Maternal protein int...

Murine Nramp1 encodes a divalent cation transporter that is expressed in late endosomes/lysosomes of macrophages, and the transported cations facilitate intracellular pathogen growth control. The Nramp1 promoter is TATA box-deficient, has two initiator elements, and is repressed by c-Myc, in accordance with the notion that genes that deplete the ir...

Murine Nramp1 encodes a divalent cation transporter that is expressed in late endosomes/lysosomes of macrophages, and the transported cations facilitate intracellular pathogen growth control. The Nramp1 promoter is TATA box-deficient, has two initiator elements, and is repressed by c-Myc, in accordance with the notion that genes that deplete the ir...

Iron is essential for growth, and impaired iron homoeostasis through a non-conserved mutation within murineNramp1, also termed Slc11a1, contributes to susceptibility to infection. Nramp1 depletes the macrophage cytosol of iron, with effects on iron-regulated gene expression and iron-dependent processes. Wu and colleagues (Wu, K.-J., Polack, A., and...

N-Myc is a member of the Myc family of transcription factors that have been shown to play a pivotal role in cell proliferation and differentiation. In this report, we have investigated the relationship between N-Myc and the developmental control gene Pax-3. Using transient transfection assays, we show that the Pax-3 promoter is activated by both N-...

The Nramp1 (natural resistance-associated macrophage protein 1) gene modulates the growth of intracellular pathogens and encodes a divalent cation transporter within lysosomes/late endosomes of macrophages. Nramp1 modulates the cytoplasmic iron pool. Wu, Polack and Dalla-Favera [(1999) Science 283, 676-679] showed reciprocal control of H-ferritin a...