How DES exposure affects the neonatal uterine epigenome

Widespread enhancer activation via ERα mediates estrogen response in vivo during uterine development, 2018

Key Points

  • Neonatal DES exposure increases H3K27ac association across the genome in the mouse uterus on postnatal day 5 (PND5)
  • ChIP-seq signal of H3K27ac at the TSS correlates with DES-mediated gene expression changes
  • DES remodels enhancer-like features of differentially expressed genes
  • DES mediates the formation of super-enhancers near altered genes
  • DES associated active enhancers are correlated with gene expression and are moderately conserved
  • DES-dependent active enhancers are highly enriched in ERα motifs
  • ERα, but not FOXA2 or FOXO1, is required for DES-mediated gene expression
  • ERα is required for DES-mediated epigenetic modifications
  • DES driven epigenetic modifications result in aberrant expression of the Padi gene family


Little is known regarding how steroid hormone exposures impact the epigenetic landscape in a living organism.

Here, we took a global approach to understanding how exposure to the estrogenic chemical, diethylstilbestrol (DES), affects the neonatal mouse uterine epigenome.

Integration of RNA- and ChIP-sequencing data demonstrated that ∼80% of DES-altered genes had higher H3K4me1/H3K27ac signal in close proximity. Active enhancers, of which ∼3% were super-enhancers, had a high density of estrogen receptor alpha (ERα) binding sites and were correlated with alterations in nearby gene expression. Conditional uterine deletion of ERα, but not the pioneer transcription factors FOXA2 or FOXO1, prevented the majority of DES-mediated changes in gene expression and H3K27ac signal at target enhancers. An ERα dependent super-enhancer was located at the Padi gene locus and a topological connection to the Padi1 TSS was documented using 3C-PCR. Chromosome looping at this site was independent of ERα and DES exposure, indicating that the interaction is established prior to ligand signaling. However, enrichment of H3K27ac and transcriptional activation at this locus was both DES and ERα-dependent.

These data suggest that DES alters uterine development and consequently adult reproductive function by modifying the enhancer landscape at ERα binding sites near estrogen-regulated genes.


  • Full text (free access) : Widespread enhancer activation via ERα mediates estrogen response in vivo during uterine development, Nucleic acids research, NCBI PubMed PMC6009594, 2018 Jun 20.
  • Featured image : Genomic distribution of histone H3K27me3, H3K4me3 and H3K27ac following neonatal DES treatment.
    • (A) Venn diagrams showing overlapping peaks between Co and DES-exposed samples for each histone mark.
    • (B) Pie charts illustrating percentage genomic distribution of each histone mark in Co and DES-exposed uterine samples. The legend on the right indicates the genomic features.
    • (C) Metaplots depicting the enrichment patterns (reads per million uniquely mapped) of the histone marks for all TSS ± 5 kb of annotated genes. Closed triangle indicates TSS.
    • PMC6009594/figure/F1.

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