Poor Endometrial Proliferation After Clomiphene is Associated With Altered Estrogen Action

Bressler, Leah Hawkins; Fritz, Marc A.; Wu, San‐Pin; Li, Yuan; Kafer, Suzanna; Wang, Tianyuan; DeMayo, Francesco J.; Young, Steven L.

doi:10.1210/clinem/dgab381

Cited by 13 publications

(10 citation statements)

References 114 publications

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“…Our previous study described PGR ChIPseq analysis of endometrial biopsies and integrated it with RNAseq (30). Other published ESR1 ChIPseq studies utilized cultured endometrial stromal cells (53), uterine adenocarcinoma epithelial cell lines (23,54,55), endometrial tumors (24), or endometrial biopsies from infertile women (15). In these and other ESR1 ChIPseq analyses, most binding is observed either at distal enhancers or within genes, and motif analysis reveals that ERE is a highly enriched motif in ESR1 ChIPseq peaks from either stage ((18,19) Figs.…”

Section: Discussionmentioning

confidence: 99%

The estrogen receptor α cistrome in human endometrium and epithelial organoids

Hewitt

Wang

et al. 2022

Preprint

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ContextEndometrial health is impacted by molecular processes that underlie estrogen responses.ObjectiveTo define estrogen regulation of endometrial function by integrating the estrogen receptor alpha (ESR1) cistrome and transcriptome of endometrial biopsies taken from the proliferative and midsecretory phases of the menstrual cycle and hormonally stimulated endometrial epithelial organoids.DesignESR1 ChIPseq and RNAseq were performed on proliferative or mid-secretory endometrial biopsies and on hormone treated organoid cultures.SettingEndometrial samples were obtained from volunteers at outpatient research clinics for ChIPseq and for organoid culture.Patients or Other ParticipantsParticipants were fertile, reproductive aged women with normal cycle length, and without any history of infertility or irregular cycles. In total, 5 new endometrial biopsies obtained from 5 women were used in this study and were analyzed together with previously published cycle stage endometrial RNAseq data.Intervention(s)There were no interventions in this study.Main Outcome Measure(s)The cycle stage specific ESR1 binding sites and gene expression identification of human endometrium and organoid cultures were integrated with changes in gene expression.ResultsGenes with ESR1 binding in whole endometrium were enriched for chromatin modification and regulation of cell proliferation. The distribution of ESR1 binding sites in organoids was more distal to the gene promoter when compared to primary endometrium. Organoid estrogen/ESR1 candidate target genes impacted formation of cellular protrusions, and chromatin modification,ConclusionsAnalysis of the ESR1 cistromes and transcriptomes from endometrium and organoids provides important resources for understanding how estrogen impacts endometrial health and function.

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Section: Discussionmentioning

confidence: 99%

The estrogen receptor α cistrome in human endometrium and epithelial organoids

Hewitt

Wang

et al. 2022

Preprint

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“…The estrogen level in the blood at this time is stable between 200 and 300 pg/ml. When the endometrial thickness reached ≥ 8 mm (Lewin et al, 2002;Hawkins Bressler et al, 2021), participants were included in the study, and then an endometrial tissue biopsy was performed. If the endometrium remained <8 mm, the hormonally controlled cycle was canceled.…”

Section: Hormonally Controlled Cyclesmentioning

confidence: 99%

Single-Cell Transcriptomics of Proliferative Phase Endometrium: Systems Analysis of Cell–Cell Communication Network Using CellChat

Fang

Tian

Sui

et al. 2022

Front. Cell Dev. Biol.

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The endometrium thickness increases by which endometrial angiogenesis occurs in parallel with the rapid growth of endometrium during the proliferative phase, which is orchestrated by complex cell–cell interactions and cytokine networks. However, the intercellular communication has not been fully delineated. In the present work, we studied the cell–cell interactome among cells of human proliferative phase endometrium using single-cell transcriptomics. The transcriptomes of 33,240 primary endometrial cells were profiled at single-cell resolution. CellChat was used to infer the cell–cell interactome by assessing the gene expression of receptor–ligand pairs across cell types. In total, nine cell types and 88 functionally related signaling pathways were found. Among them, growth factors and angiogenic factor signaling pathways, including EGF, FGF, IGF, PDGF, TGFb, VEGF, ANGPT, and ANGPTL that are highly associated with endometrial growth, were further analyzed and verified. The results showed that stromal cells and proliferating stromal cells represented cell–cell interaction hubs with a large number of EGF, PDGF incoming signals, and FGF outgoing signals. Endothelial cells exhibited cell–cell interaction hubs with a plenty of VEGF, TGFb incoming signals, and ANGPT outgoing signals. Unciliated epithelial cells, ciliated epithelial cells, and macrophages exhibited cell–cell interaction hubs with substantial EGF outgoing signals. Ciliated epithelial cells represented cell–cell interaction hubs with a large number of IGF and TGFb incoming signals. Smooth muscle cells represented lots of PDGF incoming signals and ANGPT and ANGPTL outgoing signals. This study deconvoluted complex intercellular communications at the single-cell level and predicted meaningful biological discoveries, which deepened the understanding of communications among endometrial cells.

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“…Estrogen also facilitates the progression of endometriosis by increasing growth of lesions and can impact the severity of endometriosis symptoms (14). Finally, we reported previously that thin endometrium, associated with poor fertility treatment outcomes, is associated with defects in estrogen signaling (15). Therefore, understanding mechanisms for optimal estrogen signaling is a key element in maximizing women's health.…”

Section: Introductionmentioning

confidence: 99%

The Estrogen Receptor α Cistrome in Human Endometrium and Epithelial Organoids

Hewitt

Wang

et al. 2022

Endocrinology

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Endometrial health is impacted by molecular processes that underlie estrogen responses. We assessed estrogen regulation of endometrial function by integrating the estrogen receptor alpha (ESR1) cistromes and transcriptomes of endometrial biopsies taken from the proliferative and mid-secretory phases of the menstrual cycle together with hormonally stimulated endometrial epithelial organoids. The cycle stage specific ESR1 binding sites were determined by ChIPseq and then integrated with changes in gene expression from RNAseq data to infer candidate ESR1 targets in normal endometrium. Genes with ESR1 binding in whole endometrium were enriched for chromatin modification and regulation of cell proliferation. The distribution of ESR1 binding sites in organoids was more distal from gene promoters when compared to primary endometrium and was more similar to the proliferative than the mid-secretory phase ESR1 cistrome. Inferred organoid estrogen/ESR1 candidate target genes impacted formation of cellular protrusions, and chromatin modification. Comparison of signaling impacted by candidate ESR1 target genes in endometrium vs. organoids reveals enrichment of both overlapping and distinct responses. Our analysis of the ESR1 cistromes and transcriptomes from endometrium and organoids provides important resources for understanding how estrogen impacts endometrial health and function.

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Poor Endometrial Proliferation After Clomiphene is Associated With Altered Estrogen Action

Cited by 13 publications

References 114 publications

The estrogen receptor α cistrome in human endometrium and epithelial organoids

The estrogen receptor α cistrome in human endometrium and epithelial organoids

Single-Cell Transcriptomics of Proliferative Phase Endometrium: Systems Analysis of Cell–Cell Communication Network Using CellChat

The Estrogen Receptor α Cistrome in Human Endometrium and Epithelial Organoids

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