scholarly journals Characterization of Long Non-Coding RNA Profiles in Porcine Granulosa Cells of Healthy and Atretic Antral Follicles: Implications for a Potential Role in Apoptosis

2021 ◽  
Vol 22 (5) ◽  
pp. 2677
Author(s):  
Li Meng ◽  
Kun Zhao ◽  
Chi Chiu Wang ◽  
Jian Tao ◽  
Zhenfang Wu ◽  
...  
Keyword(s):  
Linear Regression ◽  
Granulosa Cells ◽  
Target Genes ◽  
Linear Regression Analysis ◽  
Follicular Development ◽  
Ovarian Steroidogenesis ◽  
Qrt Pcr ◽  
Mrna Targets ◽  
Porcine Granulosa Cells ◽  
Estradiol Synthesis

Long non-coding RNAs (lncRNAs) play important roles in multiple biological processes including ovarian follicular development. Here we aimed to gain novel information regarding lncRNAs transcriptome profiles in porcine granulosa cells of advanced atretic antral (AA) and healthy antral (HA) follicles using RNA-seq. A total of 11,321 lncRNAs including 10,813 novel and 508 annotated lncRNAs were identified, of which 173 lncRNAs were differentially expressed (DE-lncRNAs); ten of these were confirmed by qRT-PCR. Gene Ontology indicated that DE-lncRNAs associated with developmental processes were highly enriched. Pathway analysis demonstrated predicted cis- and trans-targets of DE-lncRNAs. Potential mRNA targets of up-regulated DE-lncRNAs were mainly enriched in apoptosis related pathways, while targeted genes of downregulated DE-lncRNAs were primarily enriched in metabolism and ovarian steroidogenesis pathways. Linear regression analyses showed that expression of upregulated DE-lncRNAs was significantly associated with apoptosis related genes. NOVEL_00001850 is the most-downregulated DE-lncRNA (FDR = 0.04, FC = −6.53), of which miRNA binding sites were predicted. KEGG analysis of its downregulated target genes revealed that ovarian steroidogenesis was the second most highlighted pathway. qRT-PCR and linear regression analysis confirmed the expression and correlation of its potential targeted gene, CYP19A1, a key gene involved in estradiol synthesis. Our results indicate that lncRNAs may participate in granulosa cells apoptosis and thus antral follicular atresia.

scholarly journals MiR-214-3p Promotes Proliferation and Inhibits Estradiol Synthesis In Porcine Granulosa Cells

2020 ◽  
Author(s):  
Shengjie Shi ◽  
Xiaoge Zhou ◽  
Jingjing Li ◽  
Lutong Zhang ◽  
Yamei Hu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cytochrome P450 ◽  
Granulosa Cells ◽  
Follicular Development ◽  
Luciferase Reporter ◽  
Reporter Assay ◽  
Cell Cycle Protein ◽  
Porcine Granulosa Cells ◽  
Cytochrome P450 Family ◽  
Estradiol Synthesis

Abstract Background: Granulosa cells proliferation and estradiol synthesis significantly affect follicular development. The miR-214-3p expression in the ovarian tissues of high-yielding sows is higher than that in low-yielding sows, indicating that miR-214-3p may be involved in sow fertility. However, the functions and mechanisms of miR-214-3p on granulosa cells are unclear. In this study, miR-214-3p was transfected into porcine ovarian granulosa cells to investigate its functions in terms of proliferation and estradiol synthesis via flow cytometry, CCK-8 assay, EdU staining, ElisA, Real-Time PCR, and Western blot analyses. We also identified the targets of miR-214-3p via Luciferase Reporter Assay. Results: Our findings revealed that miR-214-3p promotes proliferation and inhibits estradiol synthesis in porcine granulosa cells. We also found that miR-214-3p up-regulates the expression of cell cycle genes including Cell cycle protein B (Cyclin B), Cell cycle protein D (Cyclin D), Cell cycle protein E (Cyclin E), and Cyclin-dependent kinase 4 (CDK4) at the transcription and translation levels, while down-regulating the mRNA and protein levels of cytochrome P450 family 11 subfamily A member 1 (CYP11A1), cytochrome P450 family 19 subfamily A member 1 (CYP19A1), and steroidogenic acute regulatory protein (StAR) (i.e., the key enzymes in estradiol synthesis). On-line prediction, bioinformatics analysis, a luciferase reporter assay, RT-qPCR, and Western blot results showed that the target genes of miR-214-3p in proliferation and estradiol synthesis are Mfn2 and NR5A1, respectively. Conclusions: Our findings suggest that miR-214-3p plays an important role in the functional regulation of porcine granulosa cells and therefore may be a target gene for regulating follicular development.

scholarly journals Characteristics of Circular RNA Expression Profiles of Porcine Granulosa Cells in Healthy and Atretic Antral Follicles

2020 ◽  
Vol 21 (15) ◽  
pp. 5217 ◽  
Author(s):  
Li Meng ◽  
Katja Teerds ◽  
Jian Tao ◽  
Hengxi Wei ◽  
Marcel Jaklofsky ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Binding Sites ◽  
Target Genes ◽  
Expression Profiles ◽  
Linear Regression Analysis ◽  
Antral Follicle ◽  
Circular Rnas ◽  
Potential Target ◽  
Porcine Granulosa Cells ◽  
Follicle Atresia

Circular RNAs (circRNAs) are thought to play essential roles in multiple biological processes, including apoptosis, an important process in antral follicle atresia. We aimed to investigate the potential involvement of circRNAs in granulosa cell apoptosis and thus antral follicle atresia. CircRNA expression profiles were generated from porcine granulosa cells isolated from healthy antral (HA) and atretic antral (AA) follicles. Over 9632 circRNAs were identified, of which 62 circRNAs were differentially expressed (DE-circRNAs). Back-splicing, RNase R resistance, and stability of DE-circRNAs were validated, and miRNA binding sites and related target genes were predicted. Two exonic circRNAs with low false discovery rate (FDR) high fold change, miRNA binding sites, and relevant biological functions—circ_CBFA2T2 and circ_KIF16B—were selected for further characterization. qRT-PCR and linear regression analysis confirmed expression and correlation of the targeted genes—the antioxidant gene GCLC (potential target of circ_CBFA2T2) and the apoptotic gene TP53 (potential target of circ_KIF16B). Increased mRNA content of TP53 in granulosa cells of AA follicles was further confirmed by strong immunostaining of both p53 and its downstream target pleckstrin homology like domain family a member 3 (PHLDA3) in AA follicles compared to negligible staining in granulosa cells of HA follicles. Therefore, we concluded that aberrantly expressed circRNAs presumably play a potential role in antral follicular atresia.

scholarly journals MiR-214-3p promotes proliferation and inhibits estradiol synthesis in porcine granulosa cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Shengjie Shi ◽  
Xiaoge Zhou ◽  
Jingjing Li ◽  
Lutong Zhang ◽  
Yamei Hu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cytochrome P450 ◽  
Granulosa Cells ◽  
Target Genes ◽  
Regulatory Protein ◽  
Follicular Development ◽  
Luciferase Reporter ◽  
Cell Cycle Protein ◽  
Cytochrome P450 Family ◽  
Estradiol Synthesis

Abstract Background Granulosa cells (GCs) proliferation and estradiol synthesis significantly affect follicular development. The miR-214-3p expression in the ovarian tissues of high-yielding sows is higher than that in low-yielding sows, indicating that miR-214-3p may be involved in sow fertility. However, the functions and mechanisms of miR-214-3p on GCs are unclear. This study focuses on miR-214-3p in terms of the effects on GCs proliferation and estradiol synthesis. Results Our findings revealed that miR-214-3p promotes proliferation and inhibits estradiol synthesis in porcine GCs. MiR-214-3p can increase the percentage of S-phase cells, the number of EdU labeled positive cells, and cell viability. However, E2 concentration was reduced after miR-214-3p agomir treatment. We also found that miR-214-3p up-regulates the expression of cell cycle genes including cell cycle protein B (Cyclin B), cell cycle protein D (Cyclin D), cell cycle protein E (Cyclin E), and cyclin-dependent kinase 4 (CDK4) at the transcription and translation levels, but down-regulates the mRNA and protein levels of cytochrome P450 family 11 subfamily A member 1 (CYP11A1), cytochrome P450 family 19 subfamily A member 1 (CYP19A1), and steroidogenic acute regulatory protein (StAR) (i.e., the key enzymes in estradiol synthesis). On-line prediction, bioinformatics analysis, a luciferase reporter assay, RT-qPCR, and Western blot results showed that the target genes of miR-214-3p in proliferation and estradiol synthesis are Mfn2 and NR5A1, respectively. Conclusions Our findings suggest that miR-214-3p plays an important role in the functional regulation of porcine GCs and therefore may be a target gene for regulating follicular development.

scholarly journals FGF21 Promotes Proliferation and Estradiol Synthesis in Porcine Granulosa Cells

2021 ◽  
Author(s):  
Yamei Hu ◽  
Xiaoge Zhou ◽  
Shengjie Shi ◽  
Yankun Li ◽  
Liang Huang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Granulosa Cells ◽  
Ovarian Tissue ◽  
Follicular Development ◽  
Cell Number ◽  
Cell Cycle Protein ◽  
Protein Levels ◽  
Porcine Granulosa Cells ◽  
Estradiol Synthesis

Abstract Background: The proliferation and estradiol synthesis in granulosa cells (GCs) directly promotes follicular development. Previous studies had found that FGF21 regulated the hypothalamic-pituitary-gonad axis in response to the control of fertility. However, the functions and mechanisms of FGF21 in GCs are unclear.Results: Here, we found that the mRNA and protein levels of FGF21 in the ovarian tissue of high-yielding sows (Sus scrofa) was higher than that in low-yielding sows. Moreover, FGF21 was predominantly expressed in porcine GCs. Additionally, ELISA assay showed estradiol was significantly increased when overexpression of FGF21 in porcine GCs. Meanwhile, overexpressed FGF21 up-regulated both the mRNA and protein levels of key estradiol synthesis-related genes in porcine GCs, including StAR, CYP11A1 and CYP19A1. Corresponsingly, knockdown FGF21 inhibited estradiol levels and its synthesis-related genes expression. Besides, overexpression of FGF21 promoted the proliferation of porcine GCs, displayed as increasing the percentage of S-phase cells in cell cycle and EdU positive cells, including cell viability, and upregulated cell cycle genes, including cell cycle protein B (Cyclin B) and protein E (Cyclin E). Corresponsingly, knockdown FGF21 in porcine GCs suppressed the cell cycle and cell viability, as well as EdU positive cell number.Conclusions: These findings highlight that FGF21 is associated with the development of GCs and may be a novel underlying regulator of porcine follicular development.

scholarly journals Expression and correlation of circulating miRNAs in healthy obese children

2021 ◽  
Author(s):  
Feifei Ma ◽  
Dingding Cao ◽  
Zhuo Liu ◽  
Yuanyuan Li ◽  
Shengrong Ouyang ◽  
...  
Keyword(s):  
Linear Regression ◽  
Multiple Linear Regression ◽  
Mirna Expression ◽  
Target Genes ◽  
Linear Regression Analysis ◽  
The Body ◽  
Circulating Mirnas ◽  
Obese Children ◽  
Susceptible Population ◽  
Taqman Qpcr

Abstract Background Obesity is an important risk factor of metabolic diseases. It is caused by the interaction of genetic, epigenetic, and environmental factors. This study aimed to identify specific circulating miRNAs for evaluating obesity in children. Methods Thirty children including 15 obese and 15 extremely thin were selected. The miRNA microarray was used to detect the expression of miRNAs in circulating plasma. The reliability of differential miRNA expression was verified using TaqMan qPCR. The correlation between miRNA and obesity was analyzed using multiple linear regression. Target genes for selected miRNAs were analyzed using informatics tools, and a functional network map was constructed. Results Thirty-six differential expression miRNAs were screened by gene chip, and seven up-regulated miRNAs were verified by TaqMan qPCR, including hsa-miR-126-3p, hsa-miR-15b-5p, hsa-miR-199a-3p, hsa-miR-20a-5p, hsa-miR-223-3p, hsa-miR-23a-3p, and hsa-miR-24-3p. Six miRNAs had significant statistical difference except hsa-miR-23a-3p. Multiple linear regression analysis showed that hsa-miR-15b-5p and hsa-miR-223-3p were associated with obesity [1.649 (4.974–16.084), -1.175 (-17.852~ -2.657)]. After adjusting for age and gender, these two miRNAs were still associated with obesity [1.400 (3.572–14.301), -0.973 (-15.634~ -1.303)]. Among them, hsa-miR-15b-5p and hsa-miR-223 had more predicted obesity-related target genes than others. In particular, hsa-miR-15b-5p had numerous target genes associated with the FoxO, insulin, Ras, and AMPK signaling pathways. Conclusions The miRNA expression profile in the body circulation of obese children differs from normal children. This result is attributed to the abnormal metabolism of obese children. hsa-miR-15b-5p and hsa-miR-223-3p could serve as a molecular marker for screening obese children and susceptible population of metabolic syndrome.

scholarly journals Activation of Steroidogenesis, Anti-Apoptotic Activity, and Proliferation in Porcine Granulosa Cells by RUNX1 Is Negatively Regulated by H3K27me3 Transcriptional Repression

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 495
Author(s):  
Yuyi Zhong ◽  
Liying Li ◽  
Yingting He ◽  
Bo He ◽  
Zhonghui Li ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Granulosa Cells ◽  
Cell Apoptosis ◽  
Transcriptional Repression ◽  
Epigenetic Modification ◽  
Follicular Development ◽  
Hormone Synthesis ◽  
Porcine Granulosa Cells ◽  
Related Transcription Factor ◽  
Apoptotic Activity

H3K27me3 is an epigenetic modification that results in the repression of gene transcription. The transcription factor RUNX1 (the runt-related transcription factor 1) influences granulosa cells’ growth and ovulation. This research uses ELISA, flow cytometry, EDU, ChIP-PCR, WB and qPCR to investigate steroidogenesis, cell apoptosis, and the proliferation effect of RUNX1 in porcine granulosa cells (pGCs) as regulated by H3K27me3. Decreased H3K27me3 stimulates the expression of steroidogenesis-related genes, including CYP11A1, PTGS2, and STAR, as well as prostaglandin. H3K27me3 transcriptionally represses RUNX1 here, whereas RUNX1 acts as an activator of FSHR, CYP11A1, and CYP19A1, promoting the production of androgen, estrogen, and prostaglandin, as well as increasing anti-apoptotic and cell proliferation activity, but decreasing progesterone. Both the complementary recovery of the H3K27me3 antagonist with the siRUNX1 signal, and the H3K27me3 agonist with the RUNX1 signal to maintain RUNX1 lead to the activation of CYP19A1, ER1, HSD17β4, and STAR here. Androgen and prostaglandin are significantly repressed but progesterone is markedly increased with the antagonist and siRUNX1. Prostaglandin is significantly promoted with the agonist and RUNX1. Furthermore, H3K27me3-RUNX1 affects the anti-apoptotic activity and stimulation of proliferation in pGCs. The present work verifies the transcriptional suppression of RUNX1 by H3K27me3 during antral follicular development and maturation, which determines the levels of hormone synthesis and cell apoptosis and proliferation in the pGC microenvironment.

scholarly journals Micro-RNA378 (miR-378) Regulates Ovarian Estradiol Production by Targeting Aromatase

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3941-3951 ◽  
Author(s):  
Shengyu Xu ◽  
Katja Linher-Melville ◽  
Burton B. Yang ◽  
De Wu ◽  
Julang Li
Keyword(s):  
Granulosa Cells ◽  
Follicular Development ◽  
Micro Rna ◽  
Transcriptional Level ◽  
Reproductive Disorders ◽  
Aromatase Expression ◽  
Directed Mutation ◽  
Porcine Granulosa Cells ◽  
Posttranscriptional Level

Estradiol is a steroid hormone that not only plays an important role in ovarian follicular development but also is associated with many reproductive disorders. Owing to the importance of aromatase in the production of estradiol, the regulation of aromatase gene expression at the transcriptional level has been an extensive area of study for over two decades. However, its regulation at the posttranscriptional level has remained unclear. Here, we show that micro-RNA378 (miR-378) is spatiotemporally expressed in porcine granulosa cells, the cells that generate estradiol in the ovary during follicular development, in an inverse manner compared with the expression of aromatase. In vitro overexpression and inhibition experiments revealed that aromatase expression, and therefore estradiol production, by granulosa cells, is posttranscriptionally down-regulated by miR-378. Furthermore, site-directed mutation studies identified two binding sites in the 3′-untranslated region (3′-UTR) of the aromatase coding sequence that are critical for the action of miR-378. Interestingly, overexpression of the aromatase 3′-UTR enhanced aromatase expression at the protein level in granulosa cells, possibly mediated by the binding of miR-378 within this region, thereby reducing the binding of this micro-RNA to the endogenous aromatase 3′-UTR.

scholarly journals Effects of nitric oxide on steroidogenesis in porcine granulosa cells during different stages of follicular development

2001 ◽  
pp. 303-308 ◽  
Author(s):  
M Masuda ◽  
T Kubota ◽  
T Aso
Keyword(s):  
Nitric Oxide ◽  
Granulosa Cells ◽  
Follicular Development ◽  
Aromatase Activity ◽  
Follicular Growth ◽  
No Donor ◽  
Porcine Granulosa Cells ◽  
Basal Release ◽  
Independent Process ◽  
Design And Methods

BACKGROUND: We have previously demonstrated that nitric oxide (NO) inhibits steroidogenesis via a cGMP-independent process, by inhibiting P450 aromatase activity in porcine granulosa cells (PGCs) derived from medium-sized (3--5 mm) ovarian follicles (M-PGC). OBJECTIVE: To determine whether the NO/NO synthase (NOS) system exerts any significant effects on steroidogenesis in PGCs derived from small follicles (<3 mm) (S-PGC) in comparison with those derived from medium follicles. DESIGN AND METHODS: PGCs, namely S-PGC and M-PGC, were incubated with the NO donor, NOC18, and a competitive blocker of NOS, N(3)-monomethyl-l-arginine (LNMMA), either alone or in the presence of FSH (200 ng/ml) or hCG (5 IU/ml). RESULTS: NOC18 significantly (P<0.01--0.001) suppressed basal (unstimulated) and gonadotropin-stimulated estradiol (E2) release from both S-PGC and M-PGC in a 2-h culture. NOC18 significantly (P<0.01--0.001) decreased basal and gonadotropin-stimulated progesterone release from S-PGC, but not from M-PGC. In addition, NOC18 significantly (P<0.05--0.001) inhibited aromatase activity in S-PGC. LNMMA had a significantly (P<0.01--0.001) stimulatory effect on the basal release of E2 and progesterone from M-PGC; however, it had no significant effect on basal steroidogenesis in S-PGC in a 24-h culture. In the presence of gonadotropin, LNMMA significantly (P<0.01--0.001) stimulated the release of E2 and progesterone from both S- and M-PGC, and this stimulatory effect was weaker in S-PGC than in M-PGC. These results demonstrate that NO inhibits E2 secretion by directly inhibiting the aromatase activity in S-PGC, as in M-PGC. It has been shown that the NO system suppresses the differentiation of S-PGC; however, the extent of suppression decreased with the progression of follicular growth. In addition, the activity of NOS in S-PGC was weaker than that in M-PGC. CONCLUSION: We strongly suggest that the NO/NOS system in PGC regulates steroidogenesis differently during different phase of follicular development.

scholarly journals Expression and Correlation of Circulating miRNAs in Healthy Obese Children

2021 ◽  
Author(s):  
Feifei Ma ◽  
Dingding Cao ◽  
Zhuo Liu ◽  
Yuanyuan Li ◽  
Shengrong Ouyang ◽  
...  
Keyword(s):  
Linear Regression ◽  
Multiple Linear Regression ◽  
Mirna Expression ◽  
Target Genes ◽  
Linear Regression Analysis ◽  
The Body ◽  
Circulating Mirnas ◽  
Obese Children ◽  
Susceptible Population ◽  
Taqman Qpcr

Abstract Objective: Obesity is an important risk factor of metabolic diseases. It is caused by the interaction of genetic, epigenetic, and environmental factors. This study aimed to identify specific circulating miRNAs for evaluating obesity in children. Methods: Thirty children including 15 obese and 15 extremely thin were selected. The miRNA microarray was used to detect the expression of miRNAs in circulating plasma. The reliability of differential miRNA expression was verified using TaqMan qPCR. The correlation between miRNA and obesity was analyzed using multiple linear regression. Target genes for selected miRNAs were analyzed using informatics tools, and a functional network map was constructed. Results: Thirty-six differential expression miRNAs were screened by gene chip, and seven up-regulated miRNAs were verified by TaqMan qPCR, including hsa-miR-126-3p, hsa-miR-15b-5p, hsa-miR-199a-3p, hsa-miR-20a-5p, hsa-miR-223-3p, hsa-miR-23a-3p, and hsa-miR-24-3p. Six miRNAs had significant statistical difference except hsa-miR-23a-3p. Multiple linear regression analysis showed that hsa-miR-15b-5p and hsa-miR-223-3p were associated with obesity [1.649 (4.974-16.084), -1.175 (-17.852~ -2.657)]. After adjusting for age and gender, these two miRNAs were still associated with obesity [1.400 (3.572-14.301), -0.973 (-15.634~ -1.303)]. Among them, hsa-miR-15b-5p and hsa-miR-223 had more predicted obesity-related target genes than others. In particular, hsa-miR-15b-5p had numerous target genes associated with the FoxO, insulin, Ras, and AMPK signaling pathways. Conclusion: The miRNA expression profile in the body circulation of obese children differs from normal children. This result is attributed to the abnormal metabolism of obese children. hsa-miR-15b-5p and hsa-miR-223-3p could serve as a molecular marker for screening obese children and susceptible population of metabolic syndrome.

scholarly journals OR31-04 Androgen Signaling Regulates Female Fertility Through Modulation of H3K27me3 in Granulosa Cells

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Sambit Roy ◽  
Niharika Sinha ◽  
Binbin Huang ◽  
Holly Cline-Fedewa ◽  
Jianrong Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Granulosa Cells ◽  
Promoter Region ◽  
Target Genes ◽  
Ovarian Function ◽  
Follicular Development ◽  
Underlying Mechanism ◽  
Female Fertility ◽  
Rna Seq ◽  
Primary Mouse

Abstract Androgens play a major role in female fertility and in women’s health, in general. However, the underlying mechanism and downstream physiological targets of androgen are not fully understood. Androgen actions are mediated by “nuclear” transcriptional signals or “extra-nuclear” kinase actions. Primary androgen receptor (AR) target genes are those at which AR occupies a genomic androgen response element (ARE) and regulates gene transcription. Subsequently, androgens also regulate other genes in an AR-ARE independent fashion, involving membrane-initiated androgen signaling. In the last couple of years, we have reported that androgens may also influence gene expression through histone modifications. We have found that H3K27me3 (tri-methyl lysine 27 histone3) is a downstream target of androgen actions. H3K27me3 is a gene silencing mark, regulated by Enhancer of Zeste Homologue 2 (Ezh2), a histone methyltransferase that promotes tri-methylation of K27 and androgens inhibit the expression and activity of Ezh2. In this study, we report that androgens also regulate the expression of a histone demethylase called Jumonji domain containing protein 3 (JMJD3/KDM6B), that is responsible of removing the H3K27me3 mark. We find that in granulosa cells (GCs), androgen through the PI3K/Akt pathway, in a transcription-independent fashion, increases hypoxia-inducible factor 1 alpha (HIF1α) protein levels, which in turn induce JMJD3 expression. ChIP studies reveal increased binding of HIF1α on the JMJD3 promoter region with DHT treatment. To understand the global impact of androgens on ovarian gene expression and the contribution of androgen-induced decrease of H3K27me3, we have performed RNA-seq and ChIP-seq analysis with H3K27me3 antibody in primary mouse GCs treated with DHT or vehicle. Results show 190 significantly differentially expressed genes in DHT treated sample vs vehicle, out of which 129 and 61 genes were significantly up- and downregulated, respectively. Moreover, comparison of the RNA-seq and ChIP-seq data reveals that a number of upregulated genes have significantly lower H3K27me3 enrichment in the enhancer and/or promoter region in the DHT treated samples vs vehicle. This establishes that in the ovary, androgen-induced modulation of H3K27me3 mark through regulation Ezh2 and JMJD3 expression/activity is an important regulatory mechanism for ovarian gene expression. To delineate the physiological importance of JMJD3 in normal ovarian function and female fertility, we have also developed a GC-specific JMJD3 knockout mice. We find that GC-specific JMJD3KO mice are sub-fertile with longer estrous cycles and dysregulated follicular development. This phenotype is very similar to GC-specific ARKO mice. Thus, we propose that one of the critical actions of androgens in regulating follicular function and female fertility is through the regulation of JMJD3 expression.

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