Progesterone Receptor Cooperates with HDAC3 to Establish Endometrial Receptivity
Bibliographic record
Abstract
Abstract Text Introduction HDAC3 is essential for successful pregnancies and impacts uterine receptivity, implantation, and decidualization for pregnancy establishment. Notably, HDAC3 is downregulated in the endometrium of infertile women with endometriosis, leadings to a non-receptive endometrium and progesterone resistance. However, the mechanism of progesterone resistance by HDAC3 remains unclear. Methods We performed transcriptomic and ChIP-seq analysis to identify direct targets of HDAC3 in uteri of control and uterine specific Hdac3 knock-out (Hdac3d/d) mice. HDAC3 ChIP-seq and transcriptome data were integrated into the ChIP-seq data from progesterone receptor (PGR) knock-out mice to identify common targets in uterus. The results of bioinformatic analysis were validated in mouse uteri by RT-qPCR, ChIP-qPCR and immunohistochemical analysis. Results Our transcriptomic and ChIP-seq analysis identified 1,136 genes as direct targets of HDAC3 in uterus. By integrating HDAC3 ChIP-seq with existing PGR ChIP-seq datasets, to identify co-regulated genes revealed an interesting overlap: 17,390 of the 23,035 peaks of HDAC3 ChIP-seq (75.5%) and 21,327 peaks of PGR ChIP-seq (81.5%) coincided, revealing 957 common target genes co-regulated by both HDAC3 and PGR. Our pathway and upstream analysis revealed that progesterone, estrogen, and STAT3 signaling pathways were regulated by HDAC3 and PGR. These bioinformatic results were validated using RT-qPCR and ChIP-qPCR. Furthermore, our co-immunoprecipitation assay revealed HDAC3 and PGR protein-protein interactions. Finally, HDAC3 and PGR proteins were strongly expressed in receptive endometrial epithelial and stromal cells of control mice, but non-receptive endometrium from Hdac3d/d and PRKO mice showed attenuation of PGR and HDAC3, respectively. Conclusion Our findings suggest that PGR cooperates with HDAC3 to establish endometrial receptivity by direct protein-protein interactions. The results underscore the importance of PGR-HDAC3 interactions in the pathophysiology of endometriosis-related infertility and will significantly advance our understanding of idiopathic female infertility and early pregnancy loss. This work was supported by NICHD R01HD101243, R01HD102170, and P01HD106485. Date of Presentation October 16, 2024
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".