Bridging the gap between epigenetics research and nutritional public health interventions

Epigenetic processes, primarily DNA methylation and covalent modifications of histones, regulate the transcriptional activity of genes in a manner that can be modified by environmental cues. This allows variation in the expression of the transcriptome without changes in the genome. Constraint in the early life environment, such as poor early nutrition, is associated with increased risk of non-communicable diseases, including cardio-metabolic disease and cancer in later life. Such induced phenotypic change involves environmental signals acting through developmental plasticity. Recent studies in humans and in animal models show that epigenetic processes, in particular DNA methylation, have a central role in the induction and stability of novel phenotypes and in increased disease risk. Identification of such processes suggests the potential for developing biomarkers of disease risk and for interventions to prevent or reverse the adverse effects of a poor early life environment. At present, knowledge in this area is limited to proof-of-principle studies in animal models and some initial studies in humans. Before such findings can be translated into reliable biomarkers and safe, effective interventions, several fundamental questions need to be answered. In order to achieve this, new technologies will be needed to support large cohort studies. Despite the early stage of knowledge in this field and the intellectual, technological and financial challenges, epigenetic research has substantial potential for public health benefits

Folic acid induces cell type-specific changes in the transcriptome of breast cancer cell lines: a proof-of-concept study

The effect of folic acid (FA) on breast cancer (BC) risk is uncertain. We hypothesised that this uncertainty may be due, in part, to differential effects of FA between BC cells with different phenotypes. To test this we investigated the effect of treatment with FA concentrations within the range of unmetabolised FA reported in humans on the expression of the transcriptome of non-transformed (MCF10A) and cancerous (MCF7 and Hs578T) BC cells. The total number of transcripts altered was MCF10A 75 (70 up-regulated), MCF7 24 (14 up-regulated) and Hs578T 328 (156 up-regulated). Only the cancer-associated gene TAGLN was altered by FA in all three cell lines. In MCF10A and Hs578T cells, FA treatment decreased pathways associated with apoptosis, cell death and senescence, but increased those associated with cell proliferation. The folate transporters SLC19A1, SLC46A1 and FOLR1 were differentially expressed between cell lines tested. However, the level of expression was not altered by FA treatment. These findings suggest that physiological concentrations of FA can induce cell type-specific changes in gene regulation in a manner that is consistent with proliferative phenotype. This has implications for understanding the role of FA in BC risk. In addition, these findings support the suggestion the differences in gene expression induced by FA may involve differential activities of folate transporters. Together these findings indicate the need for further studies of the effect of FA on BC

Fat and carbohydrate intake over three generations modify growth, metabolism and cardiovascular phenotype in female mice in an age-related manner

Environmental challenges such as a high fat diet during pregnancy can induce changes in offspring growth, metabolism and cardiovascular function. However, challenges that are sustained over several generations can induce progressive compensatory metabolic adjustments in young adults. It is not known if such effects persist during ageing. We investigated whether diets with different fat and carbohydrate contents over three generations modifies markers of ageing. Female C57BL/6 F0 mice were fed diets containing 5% or 21% fat (w/w) throughout pregnancy and lactation. Female offspring were fed the same diet as their dams until the F3 generation. In each generation, body weight, 24-hour food intake were recorded weekly, and plasma metabolites were measured by colorimetric assays, blood pressure by tail cuff plethysmography and vasoconstriction by myography on postnatal day 90 or 456. There was little effect of diet or generation on phenotypic markers in day 90 adults. There was a significant increase in whole body, liver and heart weight with ageing (d456) in the F3 21% fat group compared to the F1 and F3 5% groups. Fasting plasma glucose concentration was significantly increased with ageing in the 5% group in the F3 generation and in the 21% group in both generations. There was a significant effect of diet and generation on ex-vivo vasoconstriction in ageing females. Differences in dietary fat may induce metabolic compensation in young adults that persist over three generations. However, such compensatory effects decline during ageing

Rapid "Turn-on" of type 1 AGN in a quiescent early type galaxy SDSS1115+0544

We present a detailed study of a transient in the center of SDSS1115+0544 based on the extensive UV, optical, mid-IR light curves (LC) and spectra over 1200 days. The host galaxy is a quiescent early type galaxy at $z$ = 0.0899 with a blackhole mass of $2\times10^7M_\odot$. The transient underwent a 2.5 magnitude brightening over $\sim120$ days, reaching a peak $V$-band luminosity (extinction corrected) of $-20.9$ magnitude, then fading 0.5 magnitude over 200 days, settling into a plateau of $>600$ days. Following the optical brightening are the significant mid-IR flares at $3.4$ and $4.5\mu$m, with a peak time delay of $\sim180$ days. The mid-IR LCs are explained as the echo of UV photons by a dust medium with a radius of $5\times10^{17}$ cm, consistent with $\rm E(B-V)$ of 0.58 inferred from the spectra. This event is very energetic with an extinction corrected $L_{bol} \sim 4\times10^{44}$ erg s$^{-1}$. Optical spectra over 400 days in the plateau phase revealed newly formed broad H$\alpha, \beta$ emission with a FWHM of $\sim3750$ km s$^{-1}$ and narrow coronal lines such as [Fe VII], [Ne V]. This flare also has a steeply rising UV continuum, detected by multi-epoch $Swift$ data at $+700$ to $+900$ days post optical peak. The broad Balmer lines and the UV continuum do not show significant temporal variations. The slow evolving LCs over 1200 days, the constant Balmer lines and UV continuum at late-times rule out TDE and SN IIn as the physical model for this event. We propose that this event is a `turn-on' AGN, transitioning from a quiescent state to a type 1 AGN with a sub-Eddington accretion rate of $0.017M_\odot$/yr. This change occurred on a very short time scale of $\sim 120- 200$ days. The discovery of such a rapid `turn-on' AGN poses challenges to accretion disk theories and may indicate such event is not extremely rare.Comment: Comments are welcome. Emails to the first author. Accepted for publication in Ap

Polyunsaturated fatty acid biosynthesis is involved in phenylephrine-mediated calcium release in vascular smooth muscle cells

Stimulation of vascular smooth muscle (VSM) ?1-adrenoceptors induces myosin phosphorylation and vasoconstriction via mobilisation of intracellular calcium and production of specific eicosanoids. Polyunsaturated fatty acid (PUFA) biosynthesis in VSM cells is involved, although the precise mechanism is not known. To address this, we characterised PUFA biosynthesis in VSM cells and determined its role in intracellular calcium release and eicosanoid production. Murine VSM cells converted 18:2n-6 to longer chain PUFA including 22:5n-6. ?6 (D6d) and ?5 (D5d) desaturase, and elongase (Elovl) 5 were expressed. Elovl2 was not detected in human, mouse or rat VSM cells, or in rat or mouse aortae, but tit was not associated with hypermethylation of its promoter. D6d or D5d inhibition reduced 18:3n-6 and 20:4n-6 synthesis, respectively, and induced concentration-related decrease in phenylephrine-mediated calcium release, and in PGE2 and PGF2? secretion. Together these findings suggest that PUFA biosynthesis in VSM cells is involved in calcium release associated with vasoconstriction

Fatty acid profiles of great tit (Parus major) eggs differ between urban and rural habitats, but not between coniferous and deciduous forests

Early-life nutrition is an important determinant of both short- and long-term performance and fitness. The avian embryo develops within an enclosed package of nutrients, of which fatty acids (FA) are essential for many aspects of development. The FA composition of yolk depends on maternal nutrition and condition prior to egg formation, which may be affected by the external environment. To test if maternal environment affects yolk FA composition, we investigated whether the FA composition of great tit (Parus major) egg yolks differed between urban and rural habitats, and between deciduous and coniferous habitats. The results reveal differences in FA composition between eggs laid in urban and rural habitats, but not between eggs from the coniferous and deciduous habitats. To a large extent, this difference likely reflects dietary differences associated with urban habitats rather than dominating vegetation type. Specifically, urban yolks contained lower proportions of both ω-3 and ω-6 polyunsaturated FAs (PUFA), which are important for chick development. We also found a positive association between the proportion of saturated fatty acids and laying date, and a negative association between the proportion of ω-6 PUFA and clutch size. Given that urbanization is expanding rapidly, future studies should investigate whether factors such as anthropogenic food in the urban environment underlie these differences and whether they impair chick development

Differential pathways to adult metabolic dysfunction following poor nutrition at two critical developmental periods in sheep

Epidemiological and experimental studies suggest early nutrition has long-term effects on susceptibility to obesity, cardiovascular and metabolic diseases. Small and large animal models confirm the influence of different windows of sensitivity, from fetal to early postnatal life, on offspring phenotype. We showed previously that undernutrition in sheep either during the first month of gestation or immediately after weaning induces differential, sex-specific changes in adult metabolic and cardiovascular systems. The current study aims to determine metabolic and molecular changes that underlie differences in lipid and glucose metabolism induced by undernutrition during specific developmental periods in male and female sheep. Ewes received 100% (C) or 50% nutritional requirements (U) from 1–31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks, offspring were then fed either ad libitum (CC, UC) or were undernourished (CU, UU) to reduce body weight to 85% of their individual target. From 25 weeks, all offspring were fed ad libitum. A cohort of late gestation fetuses were studied after receiving either 40% nutritional requirements (1–31 days gestation) or 50% nutritional requirements (104–127 days gestation). Post-weaning undernutrition increased in vivo insulin sensitivity, insulin receptor and glucose transporter 4 expression in muscle, and lowered hepatic methylation at the delta-like homolog 1/maternally expressed gene 3 imprinted cluster in adult females, but not males. Early gestational undernutrition induced lower hepatic expression of gluconeogenic factors in fetuses and reduced in vivo adipose tissue insulin sensitivity in adulthood. In males, undernutrition in early gestation increased adipose tissue lipid handling mechanisms (lipoprotein lipase, glucocorticoid receptor expression) and hepatic methylation within the imprinted control region of insulin-like growth factor 2 receptor in adulthood. Therefore, undernutrition during development induces changes in mechanisms of lipid and glucose metabolism which differ between tissues and sexes dependent on the period of nutritional restriction. Such changes may increase later life obesity and dyslipidaemia risk

Dietary Fish Oil Alters DNA Methylation of Genes Involved in Polyunsaturated Fatty Acid Biosynthesis in Muscle and Liver of Atlantic Salmon (Salmo salar)

acceptedVersio

Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life?

There is considerable evidence for the induction of different phenotypes by variations in the early life environment, including nutrition, which in man is associated with a graded risk of metabolic disease; fetal programming. It is likely that the induction of persistent changes to tissue structure and function by differences in the early life environment involves life-long alterations to the regulation of gene transcription. This view is supported by both studies of human subjects and animal models. The mechanism which underlies such changes to gene expression is now beginning to be understood. In the present review we discuss the role of changes in the epigenetic regulation of transcription, specifically DNA methylation and covalent modification of histones, in the induction of an altered phenotype by nutritional constraint in early life. The demonstration of altered epigenetic regulation of genes in phenotype induction suggests the possibility of interventions to modify long-term disease risk associated with unbalanced nutrition in early life