(118) Highly Orchestrated Chromatin Dynamics of the Adult Mouse Uterus are Disrupted Following Developmental DES Exposure

Wendy N. Jefferson¹, Don Delker², Tianyuan Wang², Hamed Bostan², Elizabeth Padilla-Banks¹ and Carmen J. Williams¹

¹Reproductive & Developmental Biology Laboratory and ²Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Durham, NC 27709, USA

Abstract Text:

Hormone dependent chromatin accessibility/structure, and transcription factor (TF) occupancy regulate uterine gene expression changes during the estrous cycle. Neonatal diethylstilbestrol (DES) exposure disrupts adult estrous cyclicity and impacts gene expression but the mechanism underlying these changes is not known. Therefore, we employed a multi-faceted approach to examine these dynamics by combining RNA-seq, ATAC-seq, HiC-seq and ChIP-seq for estrogen receptor alpha (ERα), progesterone receptor (PGR) and hypoxia inducible factor 2a (HIF2A). Adult controls (diestrus and estrus) were compared to adults exposed on postnatal days 1-5 to DES (1 mg/kg/day). DES exposure resulted in diminished ERα/PGR binding in locations normally occupied by ERα/PGR in controls and excessive accumulation of ERα/PGR in DES-specific locations that were accessible and co-occupied by HIF2A; HIF2A was required for some DES-induced ERα binding and gene expression changes. Neonatal DES impacted 3,963 genes but the promoter regions were not remarkably different in accessibility or TF occupancy except excessive ERα accumulation. However, extensive changes in chromatin accessibility/structure and TF occupancy occurred at enhancers looped to these promoters. In summary, neonatal DES exposure caused a persistent change in adult chromatin accessibility/structure and TF occupancy that alters gene expression required for proper uterine function and instead results in long-term cancer development.