H3K27me3 modulates aberrant transcription and apoptosis in cyclophosphamide-induced ovarian granulosa cell injury [CUT&Tag]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE236296 | GEO | 2023/11/22
REPOSITORIES: GEO
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Project description:Chemotherapy-induced ovarian damage and infertility are significant concerns for women of childbearing age with cancer, but the underlying mechanisms are still not fully understood. Our study revealed a close association between the loss of H3K27me3 and cyclophosphamide (CTX)-induced ovarian damage.
2023-11-22 | GSE235907 | GEO
Project description:Abnormal granulosa cells (GCs) death contributes to cyclophosphamide (CTX) -induced primary ovarian insufficiency (POI). To investigate the contribution of GCs in POI, gene profiles of GCs exposed to CTX were assessed using RNA-Seq and bioinformatics analysis. The results showed the differentially expressed genes (DEGs) are enriched in ferroptosis-related pathway, which is correlated with the upregulated Heme oxygenase 1 (HO-1) and downregulated glutathione peroxidase-4 (GPX4). Using CTX-induced cell culture (COV434 and KGN cells), the levels of iron, reactive oxygen species (ROS), lipid peroxide, mitochondrial superoxide, mitochondrial morphology and mitochondrial membrane potential (MMP) were detected by DCFDA, MitoSOX, C11-BODIPY, MitoTracker, Nonylacridine Orange (NAO), JC-1 and transmission electron microscopy respectively. The results showed that iron overload and disrupting ROS, including cytoROS, mtROS and lipROS homeostasis by HO-1 upregultion could induce ferroptosis via mitochondrial dysfunction in CTX-induced GCs. Moreover, HO-1 inhibition could suppress ferroptosis induced GPX4 depletion. This implies the role of ROS in CTX-induced ferroptosis and highlighted the effect of HO-1 modulators of improving CTX-induced ovarian damage, which may provide a theoretical basis for preventing or restoring GC and ovarian function in patients with POI.
2023-10-30 | GSE243720 | GEO
Project description:The role of cyclophosphamide (CTX) as a first-line chemotherapy drug in the reproductive health of young women with cancer has been controversial, especially considered to increase the risk of premature ovarian failure (POF). Therefore, in this study, c57bl/6 mice were treated by a single intraperitoneal injection of CTX.Our study suggests that CTX mainly regulates ovarian development by activate transcription factors, while reduce cholesterol production and lipid metabolism.
2020-01-01 | GSE128240 | GEO
Project description:Certain anticancer drugs, particularly cyclophosphamide (CTX), were shown to enhance the antitumor efficacy of immunotherapy through different immunomodulatory mechanisms. A better understanding of the cellular and molecular basis of CTX-mediated immunomodulation is needed to improve the efficacy of chemoimmunotherapy. Transcript profiling and flow cytometry were used to explore CTX immune-enhancing activity in patients with hematologic malignancies. A single high-dose treatment quickly (1-2 days) induced an extensive transcriptional modulation in peripheral blood mononuclear cells, leading to the reduction of cell cycle and biosynthetic/metabolic processes and to the augmentation of transcripts related to DNA damage and cell death (p53 signaling pathway, CDKN1A, CCND3, BAX, BBC3, BID, DDB2, SESN2), of scavenger receptors involved in the recognition of death (MARCO, CD68, CD163L1, SCARB2), of antigen processing/presentation mediators (CIITA, CTSC, CTSL1, CTSZ, GLA, GAA, TPP1, NEU1, SLC11A1, LAMP-2), of T cell activation markers (CD69, OX40) and, noticeably, of a type I interferon (IFN-I) signature (OAS1, CXCL10, BAFF, IFITM2, IFI6, IRF5, IRF7, STAT2, UBE2L6, UNC93B1, ISG20L1, TYK2). Moreover, the plasma levels of IFN-I-induced proinflammatory mediators (CXCL10, CCL2, IL-8, BAFF) were increased by treatment. Accordingly, CTX preconditioning induced both monocyte and lymphocyte activation, leading to the expansion of CD14+CD16+ monocytes, of HLA-DR+, IL8RA+, MARCO+ monocytes/dendritic cells and of CD69+, OX40+, IL8RA+ lymphocytes. Altogether, these data define for the first time the immunomodulatory factors induced by CTX in humans and indicate that preconditioning chemotherapy may stimulate immunity as a consequence of danger perception associated to its cytotoxic action on blood cells, through p53 and IFN-I-related mechanisms. Four-condition experiment, Untreated (10 Biological replicates) - Cyclophosphamide-treated 1 day (10 Biological replicates) - Cyclophosphamide-treated 2 days (8 Biological replicates) - Cyclophosphamide-treated 5 days (5 Biological replicates). Each sample labeled with Cy5 and co-hybridized with Cy3-labeled M-bM-^@M-^\referenceM-bM-^@M-^] aRNA. One replicate per array.
2013-09-02 | E-GEOD-39324 | biostudies-arrayexpress
Project description:The Forkhead Box, FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown herein, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the Foxo1/3 strain enhanced the penetrance and onset of GCT formation A direct comparison of ovarian granulosa cells from wild type d25 and FOXO/PTEN knockout granulosa cell tumors.
2015-06-17 | E-GEOD-67662 | biostudies-arrayexpress
Project description:RNA was extracted from normal human granulosa cells from IVF patients (hGC1 and hGC2 samples) and from adult-type ovarian granulosa cell tumor samples (H1, H8, H20, H23, H24, H28, H30, H33, H4, H18) as described in Jamieson et al, 2010. RNA from all samples was linearly amplified using the Whole Transcriptome Amplification kit (Sigma), starting from 300ng of RNA, and with 12 amplifications cycles. cDNA was purified on columns and sent to the Nimblegen platform for hybridization and transcriptional profiling. The FOXL2 locus was gentoyped in tumor samples, and all samples were found positive for the recurrent somatic mutation p.Cys134Trp which is present in >95% of adult-type ovarian granulosa cell tumors (Shah et al, 2009).
2012-08-02 | E-MTAB-483 | biostudies-arrayexpress
Project description:Certain anticancer drugs, particularly cyclophosphamide (CTX), were shown to enhance the antitumor efficacy of immunotherapy through different immunomodulatory mechanisms. A better understanding of the cellular and molecular basis of CTX-mediated immunomodulation is needed to improve the efficacy of chemoimmunotherapy. Transcript profiling and flow cytometry were used to explore CTX immune-enhancing activity in patients with hematologic malignancies. A single high-dose treatment quickly (1-2 days) induced an extensive transcriptional modulation in peripheral blood mononuclear cells, leading to the reduction of cell cycle and biosynthetic/metabolic processes and to the augmentation of transcripts related to DNA damage and cell death (p53 signaling pathway, CDKN1A, CCND3, BAX, BBC3, BID, DDB2, SESN2), of scavenger receptors involved in the recognition of death (MARCO, CD68, CD163L1, SCARB2), of antigen processing/presentation mediators (CIITA, CTSC, CTSL1, CTSZ, GLA, GAA, TPP1, NEU1, SLC11A1, LAMP-2), of T cell activation markers (CD69, OX40) and, noticeably, of a type I interferon (IFN-I) signature (OAS1, CXCL10, BAFF, IFITM2, IFI6, IRF5, IRF7, STAT2, UBE2L6, UNC93B1, ISG20L1, TYK2). Moreover, the plasma levels of IFN-I-induced proinflammatory mediators (CXCL10, CCL2, IL-8, BAFF) were increased by treatment. Accordingly, CTX preconditioning induced both monocyte and lymphocyte activation, leading to the expansion of CD14+CD16+ monocytes, of HLA-DR+, IL8RA+, MARCO+ monocytes/dendritic cells and of CD69+, OX40+, IL8RA+ lymphocytes. Altogether, these data define for the first time the immunomodulatory factors induced by CTX in humans and indicate that preconditioning chemotherapy may stimulate immunity as a consequence of danger perception associated to its cytotoxic action on blood cells, through p53 and IFN-I-related mechanisms.
2013-09-02 | GSE39324 | GEO
Project description:We used MethylCap-seq and RRBS to profile methylomes of purified human ovarian granulosa cells. Genomic DNA methylation patterns in ovarian granulosa cells were compared between two groups of women: i) oocyte donors (n=20) who were young (age 26 ± 2.2 years) and had robust response to ovarian stimulation during assisted reproductive technology (ART) (mean number of oocytes retrieved = 25); versus ii) poor responders (n=20) who were older (age 40 ± 2.3 years) and responded poorly to ovarian stimulation during ART (oocytes retrieved ≤4 and peak estradiol level ≤ 1000 pg/ml). The first group served as healthy control. The second group represented the majority of women in their early 40s who have the natural age-related decline of ovarian functions and therefore respond poorly to ovarian stimulation during ART. We compared DNA methylomes in ovarian granulosa cells from oocyte donors versus poor responders using two approaches: MethylCap-seq for broader genomic coverage, and RRBS for absolute quantification. Due to very limited amount of materials available from each poor responder, samples containing equal amounts of granulosa cell DNA were pooled from 10 individuals in each group. A second set of experiments pooling granulosa cell DNA samples from independent donor and poor responder groups (ten individuals each) was then performed.
2015-10-14 | GSE63470 | GEO
Project description:We used mRNA-seq to profile transcriptomes of purified human ovarian granulosa cells
2015-10-14 | GSE62093 | GEO
Project description:Granulosa cells abnormalities are one of the characteristics of premature ovarian insufficiency (POI). Abnormal expression of serine/arginine-rich splicing factor 1 (SRSF1) can causes a variety of diseases, but the role of SRSF1 in mouse granulosa cells has been poorly reported. In this study, we found that SRSF1 was expressed in the nuclei of both mouse oocytes and granulosa cells. Specific knockout of SRSF1 in granulosa cells was performed using Foxl2-creERT2 mice, and morphological staining showed that follicular development was blocked. In addition, granulosa cell proliferation decreased and cell apoptosis increased. The differential gene Gene Ontology (GO) analysis of RNA-Seq results showed abnormal expression of DNA repair, cell killing and other signaling pathways. Alternative splicing (AS) analysis showed that SRSF1 affected DNA damage in granulosa cells by regulating genes related to DNA repair. In conclusion, SRSF1 in granulosa cells affects female reproduction by controlling the development of follicles through regulating granulosa cell DNA repair related genes.
2024-01-01 | GSE228975 | GEO