Environmentally sensitive hotspots in the methylome of the early human embryo

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.

Tissue- and ethnicity-independent hypervariable DNA methylation states show evidence of establishment in the early human embryo

“…Maintenance of parent of origin-specific methylation (PofOm) in the pre-implantation embryo is critical for genomic imprinting ( 71 ), and several previously identified SIV loci have been found to be associated with imprinted genes and/or PofOm ( 25 , 27 , 57 ). 58 hvCpGs (1.4%) were annotated to 32 imprinted genes ( Supplementary Table S13 ), no more than expected by chance since 1.9% of array background CpGs are annotated to imprinted genes.…”

“…We explored whether hvCpGs show sensitivity to pre-natal environment by examining their overlap with loci associated with season of conception (‘SoC’) in a rural Gambian population exposed to seasonal fluctuations in diet and other factors ( 77–79 ). hvCpGs comprise 70 (29%) out of 242 previously identified SoC-CpGs ( 57 ) overlapping array background, an approximately 3-fold enrichment relative to distribution-matched controls ( Supplementary Table S11 ).…”

“…This suggests that genomic regions targeted by epigenetic silencing or maintenance mechanisms during early embryonic reprogramming may be enriched for stochastic and/or environmentally influenced methylation variation. For example, it has been suggested that regions of PofOm may be vulnerable to stochastic or environmentally-sensitive loss of methylation on the usually-methylated allele or gain of methylation on the usually-unmethylated allele at a later time-point, leading to interindividual methylation variation ( 57 , 71 , 102 ). Similarly, certain IAP elements (a class of ERVK LTR retrotransposon) show methylation variation between isogenic mice ( 67 , 68 ) that in several cases can be influenced by pre-natal environment ( 103–105 ).…”

“…Silver et al. ( 57 ) used Illumina450K data to identify 259 CpGs associated with season-of-conception (‘SoC’) in Gambian 2-year olds, each of which showed a minimum methylation difference of 4% between individuals conceived in the peaks of the Gambian rainy and dry seasons.…”

Epigenetics of pregnancy: looking beyond the DNA code

“…The precision and the timing of such processes are pivotal for avoiding developmental defects or embryonic lethality, as an incorrect establishment of the embryonic epigenome would cause a defective zygotic genome activation (ZGA). Such a brief but crucial phase represents a window of vulnerability towards interfering maternal and environmental factors (such as chronic metabolic disorders, polycystic ovary syndrome, diet, and teratogen exposure), as highlighted by an ever-increasing number of studies [68][69][70][71]. In particular, it has been suggested that the association between assisted reproductive treatment (ART) procedures and slightly higher frequences of imprinting syndromes may be due to ART causing an abnormal epigenome in the offspring [71].…”