TY - JOUR TI - Environmentally sensitive hotspots in the methylome of the early human embryo AU - Silver, Matt J AU - Saffari, Ayden AU - Kessler, Noah J AU - Chandak, Gririraj R AU - Fall, Caroline HD AU - Issarapu, Prachand AU - Dedaniya, Akshay AU - Betts, Modupeh AU - Moore, Sophie E AU - Routledge, Michael N AU - Herceg, Zdenko AU - Cuenin, Cyrille AU - Derakhshan, Maria AU - James, Philip T AU - Monk, David AU - Prentice, Andrew M A2 - Deelen, Joris A2 - Tyler, Jessica K A2 - Mansell, Toby VL - 11 PY - 2022 DA - 2022/02/21 SP - e72031 C1 - eLife 2022;11:e72031 DO - 10.7554/eLife.72031 UR - https://doi.org/10.7554/eLife.72031 AB - 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. KW - DNA methylation KW - early embryo KW - conception KW - metastable epiallele KW - nutrition KW - parent-of-origin effects JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -