Environmentally sensitive hotspots in the methylome of the early human embryo

  1. Matt J Silver  Is a corresponding author
  2. Ayden Saffari
  3. Noah J Kessler
  4. Gririraj R Chandak
  5. Caroline HD Fall
  6. Prachand Issarapu
  7. Akshay Dedaniya
  8. Modupeh Betts
  9. Sophie E Moore
  10. Michael N Routledge
  11. Zdenko Herceg
  12. Cyrille Cuenin
  13. Maria Derakhshan
  14. Philip T James
  15. David Monk
  16. Andrew M Prentice
  1. MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, United Kingdom
  2. University of Cambridge, United Kingdom
  3. CSIR-Centre for Cellular and Molecular Biology, India
  4. University of Southampton, United Kingdom
  5. MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Gambia
  6. King's College London, United Kingdom
  7. University of Leeds, United Kingdom
  8. International Agency For Research On Cancer, France
  9. 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.

The following previously published data sets were used

Article and author information

Author details

  1. Matt J Silver

    Faculty of Epidemiology and Public Health, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom
    For correspondence
    matt.silver@lshtm.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3852-9677
  2. Ayden Saffari

    Faculty of Epidemiology and Public Health, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Noah J Kessler

    Department of Genetics, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Gririraj R Chandak

    Genomic Research on Complex Diseases, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    The authors declare that no competing interests exist.
  5. Caroline HD Fall

    MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Prachand Issarapu

    Genomic Research on Complex Diseases, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    The authors declare that no competing interests exist.
  7. Akshay Dedaniya

    Genomic Research on Complex Diseases, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    The authors declare that no competing interests exist.
  8. Modupeh Betts

    Faculty of Epidemiology and Public Health, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, Gambia
    Competing interests
    The authors declare that no competing interests exist.
  9. Sophie E Moore

    Department of Women and Children's Health, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Michael N Routledge

    School of Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Zdenko Herceg

    Epigenomics and Mechanisms Branch, International Agency For Research On Cancer, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Cyrille Cuenin

    Epigenomics and Mechanisms Branch, International Agency For Research On Cancer, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Maria Derakhshan

    Faculty of Epidemiology and Public Health, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Philip T James

    Faculty of Epidemiology and Public Health, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. David Monk

    Biomedical Research Centre, University of East Anglia, Norwich, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Andrew M Prentice

    Faculty of Epidemiology and Public Health, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, Gambia
    Competing interests
    The authors declare that no competing interests exist.

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.

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.

Reviewing Editor

  1. Joris Deelen, Max Planck Institute for Biology of Ageing, Germany

Publication history

  1. Preprint posted: September 23, 2019 (view preprint)
  2. Received: July 7, 2021
  3. Accepted: February 18, 2022
  4. Accepted Manuscript published: February 21, 2022 (version 1)
  5. 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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  1. Matt J Silver
  2. Ayden Saffari
  3. Noah J Kessler
  4. Gririraj R Chandak
  5. Caroline HD Fall
  6. Prachand Issarapu
  7. Akshay Dedaniya
  8. Modupeh Betts
  9. Sophie E Moore
  10. Michael N Routledge
  11. Zdenko Herceg
  12. Cyrille Cuenin
  13. Maria Derakhshan
  14. Philip T James
  15. David Monk
  16. Andrew M Prentice
(2022)
Environmentally sensitive hotspots in the methylome of the early human embryo
eLife 11:e72031.
https://doi.org/10.7554/eLife.72031

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