Environmentally sensitive hotspots in the methylome of the early human embryo
- MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, United Kingdom
- University of Cambridge, United Kingdom
- CSIR-Centre for Cellular and Molecular Biology, India
- University of Southampton, United Kingdom
- MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Gambia
- King's College London, United Kingdom
- University of Leeds, United Kingdom
- International Agency For Research On Cancer, France
- University of East Anglia, United Kingdom
Abstract
In humans, DNA methylation marks inherited from gametes are largely erased following fertilisation, prior to construction of the embryonic methylome. Exploiting a natural experiment of seasonal variation including changes in diet and nutritional status in rural Gambia, we analysed three datasets covering two independent child cohorts and identified 259 CpGs showing consistent associations between season of conception (SoC) and DNA methylation. SoC effects were most apparent in early infancy, with evidence of attenuation by mid-childhood. SoC-associated CpGs were enriched for metastable epialleles, parent-of-origin specific methylation and germline DMRs, supporting a periconceptional environmental influence. Many SoC-associated CpGs overlapped enhancers or sites of active transcription in H1 ESCs and fetal tissues. Half were influenced but not determined by measured genetic variants that were independent of SoC. Environmental ‘hotspots’ providing a record of environmental influence at periconception constitute a valuable resource for investigating epigenetic mechanisms linking early exposures to lifelong health and disease.
Data availability
Illumina 450k methylation array data generated from Gambian 2 year olds from the ENID trial is deposited in GEO (GSE99863). Requests to access and analyse the other Gambian methylation datasets (ENID 5-7yr and EMPHASIS 7-9yr) should be submitted to the corresponding author in the first instance. An application would then need to be made to MRC Unit The Gambia's Scientific Coordinating Committee and the Joint MRC/Gambia Government Ethics Committee.Sources and locations of other publicly available data used in this analysis are described in Methods. Bespoke code used in the analysis is available at https://zenodo.org/record/5801480.
Article and author information
Author details
Funding
Medical Research Council (MC-A760-5QX00)
- Matt J Silver
- Andrew M Prentice
Bill and Melinda Gates Foundation (OPP1 066947)
- Sophie E Moore
- Michael N Routledge
- Zdenko Herceg
Medical Research Council (MR/N006208/1)
- Matt J Silver
- Caroline HD Fall
- Andrew M Prentice
Department of Biotechnology, Ministry of Science and Technology, India (BT/IN/DBT-MRC/DFID/24/GRC/2015-16)
- Gririraj R Chandak
Medical Research Council (MR/M01424X/1)
- Matt J Silver
- Ayden Saffari
- Noah J Kessler
- Andrew M Prentice
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Joris Deelen, Max Planck Institute for Biology of Ageing, Germany
Ethics
Human subjects: Ethics approval for the Gambian ENID and EMPHASIS trials was obtained from the joint Gambia Government/MRC Unit The Gambia's Ethics Committee (ENID: SCC1126v2; EMPHASIS: SCC1441). The ENID study is registered as ISRCTN49285450. The EMPHASIS study is registered as ISRCTN14266771. Signed informed consent for both studies was obtained from parents, and verbal assent was additionally obtained from the older children who participated in the EMPHASIS study.
Version history
- Preprint posted: September 23, 2019 (view preprint)
- Received: July 7, 2021
- Accepted: February 18, 2022
- Accepted Manuscript published: February 21, 2022 (version 1)
- Version of Record published: March 10, 2022 (version 2)
Copyright
© 2022, Silver et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Environmentally sensitive hotspots in the methylome of the early human embryo
eLife 11:e72031.
https://doi.org/10.7554/eLife.72031
Further reading
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- Epidemiology and Global Health
Background:
Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of omega-6/omega-3 ratio in mortality.
Methods:
We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6461 died during follow-up, including 2794 from cancer and 1668 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors.
Results:
Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all Ptrend <0.05). Comparing the highest to the lowest quintiles, individuals had 26% (95% CI, 15–38%) higher total mortality, 14% (95% CI, 0–31%) higher cancer mortality, and 31% (95% CI, 10–55%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects.
Conclusions:
Using a population-based cohort in UK Biobank, our study revealed a strong association between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD mortality.
Funding:
Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institute of Health under the award number R35GM143060 (KY). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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