Epigenetic remodelling of enhancers in response to estrogen deprivation and re-stimulation

Estrogen hormones are implicated in a majority of breast cancers and estrogen receptor alpha (ER), the main nuclear factor mediating estrogen signaling, orchestrates a complex molecular circuitry that is not yet fully elucidated. Here, we investigated genome-wide DNA methylation, histone acetylation and transcription after estradiol (E2) deprivation and re-stimulation to better characterize the ability of ER to coordinate gene regulation. We found that E2 deprivation mostly resulted in DNA hypermethylation and histone deacetylation in enhancers. Transcriptome analysis revealed that E2 deprivation leads to a global down-regulation in gene expression, and more specifically of TET2 demethylase that may be involved in the DNA hypermethylation following short-term E2 deprivation. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER connection mainly with two partner TF families, AP-1 and FOX. Theseinteractions takeplace in the proximity of E2 deprivation-mediated differentially methylated and histone acetylated enhancers. Finally, while most deprivation-dependent epigenetic changes were reversed following E2 re-stimulation, DNA hypermethylation and H3K27 deacetylation at certain enhancers were partially retained. Overall, these results show that inactivation of ER mediates rapid and mostly reversible epigenetic changes at enhancers, and bring new insight into early events, which may ultimately lead to endocrine resistance.Institut National du Cancer (INCa, France, in part); European Commission (EC) Seventh Framework Programme (FP7) Translational Cancer Research (TRANSCAN) Framework; Fondation ARC pour la Recherche sur le Cancer (France) (to Z.H.); Fonds National de la Recherche, Luxembourg [10100060 to A.S.]; IARC Fellowship (Marie Curie actions – People – COFUND to N.F.J., in part); PoSTDoctoral Fellowship of the Basque Government; Swiss National Science Foundation (SNSF) (to L.V., V.Y., R.M.). Funding for open access charge: IARC regular budge