News Article | April 25, 2017
These changes, known as epigenetic modifications, control the activity of our genes without changing the actual DNA sequence. One of the main epigenetic modifications is DNA methylation, which plays a key role in embryonic development and the formation of different cell types, regulating when and where genes are switched on. Although DNA methylation was originally thought to be a very stable modification, which once established in early life was then maintained throughout the life span of an individual, there is now growing evidence that the level of DNA methylation can be affected by a range of environmental factors such as parental health, diet and lifestyle. Researchers from the University of Southampton, as part of the EpiGen Global Consortium, analysed the levels of DNA methylation, in umbilical cord tissue of babies born in the Southampton Women's Survey. They compared DNA methylation levels present at birth with the amount of fat tissue in the child at four and six years of age. They found that lower DNA methylation at the CDKN2A gene, which regulates the production of fat cells, was associated with a greater risk of the child developing obesity in later life. Analysis showed that a 10 percent decrease in methylation at the CDKN2A gene was associated with an increase in fat mass of around 220g, at age 4 years. The results, published in EBio Medicine, were replicated in other groups of children and adults, notably the Singapore GUSTO study, the Australian RAINE study and the UK BIOCLAIMS cohort. Lead author Karen Lillycrop said: "This is exciting new evidence that epigenetic changes detectable at birth are linked to a child's health as they grow up. It was very promising to see our initial findings confirmed in so many other cohorts. Not only does it strengthen the body of evidence that shows a mothers health during pregnancy can affect the future health of her child, but it could also allow us to more accurately predict the future risk of obesity. If we can do this, then preventative strategies can be developed in early life to prevent the development of obesity." Professor Keith Godfrey, from the Medical Research Council Lifecourse Epidemiology Unit and the National Institute for Health Research Southampton Biomedical Research Centre and a member of the study team said: "The new findings provide the first direct evidence linking faltering of a baby's growth in the womb with epigenetic modifications that themselves may increase the risk of childhood obesity. The findings are now helping us to trial new nutritional interventions before and during pregnancy to reduce the baby's risk on obesity in childhood and later life, and strengthen the view that effective prevention of childhood obesity has to begin before the baby is born. The new findings may also lead to innovative approaches to the treatment of established obesity in later life." The EpiGen Global Consortium brings together expertise from the Human Development and Health Academic Unit, MRC Lifecourse Epidemiology Unit and Centre for Biological Sciences, University of Southampton; Singapore Institute for Clinical Sciences; National University of Singapore; Auckland UniServices Limited and the Liggins Institute, University of Auckland. The Consortium's aim is to improve human health through the life course by further understanding developmental and environmental processes. The research includes a focus on epigenetics, the biology of understanding how gene function is regulated by environmental factors, such as maternal nutrition, during the very early stages of development. This research was carried out as part of a collaboration with the Nestlé Research Centre, in Lausanne, Switzerland.
News Article | May 10, 2017
Researchers from the MRC Lifecourse Epidemiology Unit and the Institute of Developmental Sciences at the University of Southampton, as part of the Epigen Global Consortium, looked at whether bone health might be influenced by epigenetic modifications of DNA early in life. The results, published in the Journal of Bone and Mineral Research, provide an insight into the early determinants of skeletal growth, and improve the understanding of how osteoporosis could be prevented in future generations. There is growing evidence that whether genes are expressed or not (switched on or off) in particular human cells can change throughout life and can be affected by a range of environmental factors even before birth, such as their parents' health, diet and lifestyle before and during pregnancy. This switching on or off of genes is known as "epigenetic modification" and an important epigenetic mechanism is DNA methylation. The Southampton researchers analysed the levels of DNA methylation in umbilical cord tissue of 669 babies born in the Southampton Women's Survey. They compared the DNA methylation levels in the CDKN2A gene to the bone mass of the child at four and six years of age, measured using DXA bone densitometry. They found that higher DNA methylation in particular parts of the CDKN2A gene, which is known to play a role in development and ageing, was associated with lower bone mass at four and six years. Analysis showed that a 10 percent increase in methylation was associated with a decrease in total bone mass of around 4-9g at age four years. Further laboratory analysis showed that methylation of the CDKN2A region is important for the function and survival of bone cells. Nicholas Harvey, Professor of Rheumatology and Clinical Epidemiology at the University of Southampton, led the study with Dr Elizabeth Curtis, Wellcome Trust Clinical Research Fellow, and Dr Robert Murray, Postdoctoral Research Fellow, both also from the University. He said: "The health of a child's bone when they are young can influence the risk of osteoporosis in older age. This study provides exciting insights into the role of epigenetics in bone health, and might allow us to more accurately predict an individual's future risk of osteoporosis. Our ongoing studies should enable us to work out whether interventions during pregnancy, for example vitamin D supplementation, will actually alter the epigenetic marks, and lead to improved bone health in the offspring." Professor Cyrus Cooper, Director of the MRC Lifecourse Epidemiology Unit, said: "This major finding links our previous observations on maternal nutrition and lifestyle during pregnancy, with the later risk of musculoskeletal ageing in the offspring. It bears testimony to the value of large, well-maintained population cohorts, participants among whom are followed up for many years." The EpiGen Global Consortium brings together expertise from the Human Development and Health Academic Unit, MRC Lifecourse Epidemiology Unit and Centre for Biological Sciences, University of Southampton; Singapore Institute for Clinical Sciences; National University of Singapore; Auckland UniServices Limited and the Liggins Institute, University of Auckland. The Consortium's aim is to improve human health through the life course by further understanding developmental and environmental processes. The research includes a focus on epigenetics, the biology of understanding how gene function is regulated by environmental factors, such as maternal nutrition, during the very early stages of development. This research was carried out as part of a collaboration with the Nestlé Research Centre, in Lausanne, Switzerland.
Ranasinghe H.S.,Liggins Institute |
Scheepens A.,Liggins Institute |
Scheepens A.,Plant and Food Research |
Sirimanne E.,Liggins Institute |
And 7 more authors.
Developmental Neuroscience | Year: 2013
Perinatal hypoxic ischemic (HI) brain injury is a leading cause of long-term neurological handicap in newborn babies. Recently, excessive activity of matrix metalloproteinases (MMPs), and in particular MMP-9, has been implicated in the aetiology of HI injuries to the immature brain. Our previous study suggested that MMP-9 may be involved in the development of the delayed injury processes following HI injury to the developing brain. Given this, we therefore propose that MMP-9 may be a useful target for rescue therapies in the injured developing brain. To address this, we chose to use SB-3CT, a highly selective inhibitor that is known to target only MMP-2 and MMP-9, to attenuate the elevated MMP-9 activity seen following HI injury to the developing brain. Twenty-one-day-old postnatal Wistar rats were subjected to unilateral carotid artery occlusion followed by exposure to hypoxia (8% oxygen for 1 h). SB-3CT (50 mg/kg body weight in 25% dimethyl sulphoxide/75% polyethylene glycol) or an equal volume of vehicle or saline diluent was then administered intraperitoneally at 2, 5 and 14 h following the insult. Gelatin zymography revealed that pro-MMP-9 levels were significantly reduced at 6 h following hypoxic ischaemia (p ≤ 0.05). However, our results showed that despite significantly inhibiting brain pro-MMP-9 activity after hypoxic ischaemia, SB-3CT failed to confer significant neuroprotection in postnatal day 21 rats 3 days after an HI insult. Further investigations are warranted using a recently reported selective water-soluble version of SB-3CT or another MMP-9 selective inhibitor to resolve the role of MMP-9 in the aetiology of HI injury in the developing brain. Copyright © 2012 S. Karger AG, Basel.
Sadler L.C.,University of Auckland |
McKinlay C.J.D.,Liggins Institute
American Journal of Obstetrics and Gynecology | Year: 2016
Background The recently published INTERGROWTH-21st Project international population standard for newborn size is intended for global use, but its ability to identify small infants at risk of adverse outcomes in a general obstetric population has not been reported. Objective The objective of the study was to compare adverse neonatal outcomes among small-for-gestational-age (SGA) infants between the INTERGROWTH-21st standard and a customized birthweight standard (accounting for maternal characteristics of height, weight, parity, and ethnicity). We hypothesized that in a multiethnic general obstetric population in Auckland, New Zealand, a customized birthweight standard would better identify SGA infants at-risk of neonatal morbidity/mortality and stillbirth than the INTERGROWTH-21st standard. Study Design Using prospectively gathered maternity data from a general obstetric population in Auckland, New Zealand, from 2006 to 2013 (n = 53,484 births at ≥ 33 weeks), infants were classified as SGA (birthweight < 10th centile) by INTERGROWTH-21st and customized standards. Infants were further categorized as SGA by both criteria, INTERGROWTH-21st only, customized only, or not SGA (met neither criteria). Composite adverse neonatal outcome was defined as neonatal death, neonatal intensive care admission > 48 hours, or ventilation > 4 hours or 5-minute Apgar score < 7. Relative risks for primary outcomes were estimated using modified Poisson regression, with the non-SGA group as the referent. Results Incidence of SGA was 4.5% by INTERGROWTH-21st and 11.6% by customized standard. Compared with those not SGA, infants identified as small for gestational age by both criteria had the highest risk of adverse neonatal outcome (relative risk [RR], 4.1, 95% confidence interval [CI], 3.7-4.6) and stillbirth (RR, 8.3, 95% CI, 5.1-13.4). Infants SGA by customized standard only (n = 4015) had an increased risk of adverse neonatal outcome (RR, 2.0, 95% CI, 1.8-2.2) and stillbirth (RR, 3.0, 95% CI, 1.7-5.3). Few infants were identified as SGA by INTERGROWTH-21st only (n = 172), and risks of adverse neonatal outcome and stillbirth were not increased. Findings were unchanged when analyses were limited to term infants (n = 50,739). The INTERGROWTH-21st standard identified more Indian (12.8%) and Asian (5.8%) but fewer European (3.0%) and Pacific (2.9%) infants as SGA (P <.01). Customized criteria identified more than 3 times as many SGA infants among Maori (14.5%), Pacific (13.5%), and European (11.2%) infants and twice as many among Asian (10.3%) infants (P<0.01) compared with INTERGROWTH-21st criteria. The majority of SGA infants by INTERGROWTH-21st only were born to Indian and Asian mothers (95.4%). Conclusions In our general obstetric population, birthweight customization identified more SGA infants at risk of perinatal mortality and morbidity compared with the INTERGROWTH-21st standard. The INTERGROWTH-21st standard failed to detect many at-risk SGA infants, particularly among ethnic groups with larger maternal size while disproportionately identifying higher rates of SGA among those with smaller maternal size. Local validation is needed prior to implementation of the INTERGROWTH-21st standard to avoid misclassification of infant birth size. © 2016 Elsevier Inc. All rights reserved.
PubMed | University of Queensland, Griffith University, La Trobe University, University of Bristol and 18 more.
Type: Journal Article | Journal: Lancet (London, England) | Year: 2016
Variation in stillbirth rates across high-income countries and large equity gaps within high-income countries persist. If all high-income countries achieved stillbirth rates equal to the best performing countries, 19,439 late gestation (28 weeks or more) stillbirths could have been avoided in 2015. The proportion of unexplained stillbirths is high and can be addressed through improvements in data collection, investigation, and classification, and with a better understanding of causal pathways. Substandard care contributes to 20-30% of all stillbirths and the contribution is even higher for late gestation intrapartum stillbirths. National perinatal mortality audit programmes need to be implemented in all high-income countries. The need to reduce stigma and fatalism related to stillbirth and to improve bereavement care are also clear, persisting priorities for action. In high-income countries, a woman living under adverse socioeconomic circumstances has twice the risk of having a stillborn child when compared to her more advantaged counterparts. Programmes at community and country level need to improve health in disadvantaged families to address these inequities.
Miller C.A.,Washington University in St. Louis |
White B.S.,Washington University in St. Louis |
White B.S.,University of Washington |
Dees N.D.,Washington University in St. Louis |
And 21 more authors.
PLoS Computational Biology | Year: 2014
The sensitivity of massively-parallel sequencing has confirmed that most cancers are oligoclonal, with subpopulations of neoplastic cells harboring distinct mutations. A fine resolution view of this clonal architecture provides insight into tumor heterogeneity, evolution, and treatment response, all of which may have clinical implications. Single tumor analysis already contributes to understanding these phenomena. However, cryptic subclones are frequently revealed by additional patient samples (e.g., collected at relapse or following treatment), indicating that accurately characterizing a tumor requires analyzing multiple samples from the same patient. To address this need, we present SciClone, a computational method that identifies the number and genetic composition of subclones by analyzing the variant allele frequencies of somatic mutations. We use it to detect subclones in acute myeloid leukemia and breast cancer samples that, though present at disease onset, are not evident from a single primary tumor sample. By doing so, we can track tumor evolution and identify the spatial origins of cells resisting therapy. © 2014 Miller et al.