Developmental Cell
Volume 56, Issue 9, 3 May 2021, Pages 1238-1252.e5
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Article
Human placental cytotrophoblast epigenome dynamics over gestation and alterations in placental disease

https://doi.org/10.1016/j.devcel.2021.04.001Get rights and content
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Highlights

  • The epigenome of human placental cytotrophoblasts rapidly evolves over gestation

  • At genome scale, DNA methylation increases, and modified histones are lost

  • H3K9me3 occupancy of deeply hypomethylated DNA silences cytotrophoblast genes

  • Global increases in H3K27ac occupancy typify placental disease, for example, severe preeclampsia

Summary

The human placenta and its specialized cytotrophoblasts rapidly develop, have a compressed lifespan, govern pregnancy outcomes, and program the offspring’s health. Understanding the molecular underpinnings of these behaviors informs development and disease. Profiling the extraembryonic epigenome and transcriptome during the 2nd and 3rd trimesters revealed H3K9 trimethylation overlapping deeply DNA hypomethylated domains with reduced gene expression and compartment-specific patterns that illuminated their functions. Cytotrophoblast DNA methylation increased, and several key histone modifications decreased across the genome as pregnancy advanced. Cytotrophoblasts from severe preeclampsia had substantially increased H3K27 acetylation globally and at genes that are normally downregulated at term but upregulated in this syndrome. In addition, some cases had an immature pattern of H3K27ac peaks, and others showed evidence of accelerated aging, suggesting subtype-specific alterations in severe preeclampsia. Thus, the cytotrophoblast epigenome dramatically reprograms during pregnancy, placental disease is associated with failures in this process, and H3K27 hyperacetylation is a feature of severe preeclampsia.

Keywords

human placenta
cytotrophoblast
DNA methylation
histone modification
gestational regulation
preeclampsia
chorionic villi
H3K9me3
H3K27ac
placental disease

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