Environmentally sensitive hotspots in the methylome of the early human embryo

Silver, Matt J., Saffari, Ayden, Kessler, Noah J., Chandak, Gririraj R., Fall, Caroline H. D., Issarapu, Prachand, Dedaniya, Akshay, Betts, Modupeh, Moore, Sophie E., Routledge, Michael N., Herceg, Zdenko, Cuenin, Cyrille, Derakhshan, Maria, James, Philip T., Monk, David and Prentice, Andrew M. (2022) Environmentally sensitive hotspots in the methylome of the early human embryo. eLife, 11. ISSN 2050-084X

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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.

Item Type: Article
Additional Information: 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. The following previously published data sets were used: Van Baak T (2018) NCBI Gene Expression Omnibus ID GSE99863. DNA methylation in children from The Gambia. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE99863 Funding: The Gambian ENID trial was jointly funded by the UK Medical Research Council (MRC) and the Department for International Development (DFID) under the MRC/DFID Concordat agreement (MRC Program MC-A760-5QX00). Methylation analysis of ENID samples was supported by the Bill & Melinda Gates Foundation (grant no. OPP1 066947). The Gambian EMPHASIS study is jointly funded by MRC, DFID, and the Department of Biotechnology, Ministry of Science and Technology, India, under the Newton Fund initiative (MRC grant no. MR/N006208/1 and DBT grant no. BT/IN/DBT-MRC/DFID/24/GRC/2015–16). Further support for this analysis was provided by MRC Grant MR/M01424X/1. We acknowledge the work of the full EMPHASIS Study Group (https://www.emphasisstudy.org/) in acquiring this data.
Uncontrolled Keywords: neuroscience(all),biochemistry, genetics and molecular biology(all),immunology and microbiology(all) ,/dk/atira/pure/subjectarea/asjc/2800
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 10 Mar 2022 14:30
Last Modified: 23 Oct 2022 03:38
URI: https://ueaeprints.uea.ac.uk/id/eprint/83980
DOI: 10.7554/eLife.72031


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