Placental epi/genomics as sensors of the in utero environment and predictors of fetal development

Abstract

Introduction: The placenta is the principal organ regulating fetal development with implications for postnatal health outcomes. Appropriate transitioning through gestation requires the tightly coordinated orchestration of the placental epigenome, which sits as the interface between genes and the environment by enabling heritable and persistent changes in gene expression without altering the DNA sequence. Placental epigenetic elements include DNA methylation, histone modifications and non-coding RNAs, which undergo re-programming following fertilization as the zygote differentiates into cell-specific lineages. This is particularly pertinent at imprinted loci, key regulators of fetal development that are mono-allelically expressed based on parent-of-origin. The dynamic state of placental epigenetic marks highlights their sensitivity to perturbations during pregnancy and their potential utility as sensors of the in utero environment. Methods: We comprehensively profiled the placental miRNome, imprintome and methylome across multiple birth cohort studies. We explored their associations to in utero trace metal exposures as well as to birth outcomes and postnatal neurodevelopment. We also constructed placental gene and eQTL networks by leveraging multi-scale epi/genomic and transcriptomic data. Results: Our findings demonstrate that the placental epi/genome is highly sensitive to environmental stressors, and signature gene patterns are correlated with birth and neurodevelopmental outcomes. Lastly, placental eQTL networks reveal functional enrichment of pathways related to late-onset diseases including asthma and metabolic dysregulation. Conclusion: Emerging technologies are increasingly facilitating the comprehensive profiling of the placental epi/genome. Novel methodologies to derive meaningful signals from the generated data highlight the relevance of the placenta as a sensor of the intrauterine environment and indicator of future health outcomes.