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Environmentally sensitive hotspots in the methylome of the early human embryo

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posted on 2024-10-01, 11:08 authored by Matt J Silver, Ayden Saffari, Noah J Kessler, Gririraj R Chandak, Caroline HD Fall, Prachand Issarapu, Akshay Dedaniya, Modupeh Betts, Sophie E Moore, Michael N Routledge, Zdenko Herceg, Cyrille Cuenin, Maria Derakhshan, Philip T James, David Monk, Andrew M Prentice
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 differentially methylated regions, supporting a periconceptional environmental influence. Many SoC-associated CpGs overlapped enhancers or sites of active transcription in H1 embryonic stem cells 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.

Funding

Medical Research Council (MC-A760-5QX00)

Bill and Melinda Gates Foundation (OPP1 066947)

Epigenetic mechanisms linking maternal pre-conceptional micronutrient supplementation with offspring health in India and The Gambia

Medical Research Council

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Department of Biotechnology, Ministry of Science and Technology, India (BT/IN/DBT-MRC/DFID/24/GRC/2015-16)

Medical Research Council (MR/M01424X/1)

History

Citation

Matt J Silver, Ayden Saffari, Noah J Kessler, Gririraj R Chandak, Caroline HD Fall, Prachand Issarapu, Akshay Dedaniya, Modupeh Betts, Sophie E Moore, Michael N Routledge, Zdenko Herceg, Cyrille Cuenin, Maria Derakhshan, Philip T James, David Monk, Andrew M Prentice (2022) Environmentally sensitive hotspots in the methylome of the early human embryo eLife 11:e72031

Author affiliation

College of Life Sciences, Medicine

Version

  • VoR (Version of Record)

Published in

eLife

Volume

11

Pagination

e72031

Publisher

eLife Sciences Publications, Ltd

issn

2050-084X

eissn

2050-084X

Acceptance date

2022-02-21

Copyright date

2022

Available date

2024-10-01

Spatial coverage

England

Language

en

Deposited by

Dr Michael Routledge

Deposit date

2024-08-23

Data Access Statement

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.

Rights Retention Statement

  • No