Single-Cell Transcriptomic Atlas of Primate Ovarian Aging. Wang S et al. (2020) Molecular mechanisms of ovarian aging and female age-related fertility decline remain unclear. We surveyed the single-cell transcriptomic landscape of ovaries from young and aged non-human primates (NHPs) and identified seven ovarian cell types with distinct gene-expression signatures, including oocyte and six types of ovarian somatic cells. In-depth dissection of gene-expression dynamics of oocytes revealed four subtypes at sequential and stepwise developmental stages. Further analysis of cell-type-specific aging-associated transcriptional changes uncovered the disturbance of antioxidant signaling specific to early-stage oocytes and granulosa cells, indicative of oxidative damage as a crucial factor in ovarian functional decline with age. Additionally, inactivated antioxidative pathways, increased reactive oxygen species, and apoptosis were observed in granulosa cells from aged women. This study provides a comprehensive understanding of the cell-type-specific mechanisms underlying primate ovarian aging at single-cell resolution, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders. This gene is down-regulated in aging oocytes//////////////////
NCBI Summary:
This gene encodes a member of the E protein (class I) family of helix-loop-helix transcription factors. E proteins activate transcription by binding to regulatory E-box sequences on target genes as heterodimers or homodimers, and are inhibited by heterodimerization with inhibitor of DNA-binding (class IV) helix-loop-helix proteins. E proteins play a critical role in lymphopoiesis, and the encoded protein is required for B and T lymphocyte development. Deletion of this gene or diminished activity of the encoded protein may play a role in lymphoid malignancies. This gene is also involved in several chromosomal translocations that are associated with lymphoid malignancies including pre-B-cell acute lymphoblastic leukemia (t(1;19), with PBX1), childhood leukemia (t(19;19), with TFPT) and acute leukemia (t(12;19), with ZNF384). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, Sep 2011]
General function
Nucleic acid binding, DNA binding, Transcription factor, Repressor
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stemness factor
Cellular localization
Nuclear
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Ovarian function
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Lhcgr Expression Granulosa Cells: Roles for PKA-Phosphorylated -catenin, TCF3, and FOXO1. Law NC et al. Ovarian follicles lacking FSH or FSH receptors fail to progress to a preovulatory stage, resulting in infertility. One hallmark of the preovulatory follicle is the presence of luteinizing hormone choriogonadotropin receptors (LHCGR) on granulosa cells (GCs). However, the mechanisms by which FSH induces Lhcgr gene expression are poorly understood. Our results show that protein kinase A (PKA) and phosphoinositide 3-kinase (PI3K)/AKT pathways are required for FSH to activate both the murine Lhcgr-luciferase reporter and expression of Lhcgr mRNA in rat GCs. Based on results showing that an adenovirus (Ad) expressing a steroidogenic factor 1 (SF1) mutant that cannot bind -catenin abolished FSH-induced Lhcgr mRNA, we evaluated the role of -catenin in the regulation of Lhcgr gene expression. FSH promoted the PKA-dependent, PI3K-independent phosphorylation of -catenin on Ser552 and Ser665. FSH activated the -catenin/T cell factor (TCF) artificial promoter-reporter TOPFlash via a PKA-dependent, PI3K-independent pathway; dominant-negative (DN) TCF abolished FSH-activated Lhcgr-luciferase reporter and induction of Lhcgr mRNA; microarray analysis of GCs treated with Ad-DN-TCF and FSH identified the Lhcgr as the most down-regulated gene. Chromatin immunoprecipitation results placed -catenin phosphorylated on Ser552 and Ser675 and SF1 on the Lhcgr promoter in FSH-treated GCs; TCF3 was constitutively associated with the Lhcgr promoter. Transduction with an Ad-phospho--catenin mutant (Ser552/665/Asp) enhanced Lhcgr mRNA expression in FSH-treated cells greater than 3-fold. Finally, we identified a recognized PI3K/AKT target forkhead box O1 as a negative regulator of Lhcgr mRNA expression. These results provide a new understanding of the complex regulation of Lhcgr gene expression in GCs.
Expression regulated by
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Ovarian localization
Oocyte, Granulosa
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Deciphering the cis-regulatory elements of co-expressed genes in PCOS by in silico analysis. Sarkar C et al. In recent times, the focus of research in polycystic ovary syndrome (PCOS) has shifted from candidate gene(s) approach to whole genome analysis for deciphering its molecular pathophysiology. In this regard, several microarray studies have been published, showing differential expression of genes between normal and PCOS states. Co-expression of genes as obtained in microarray experiments can also imply co-regulation at the transcriptional level by various transcription factors. In order to identify such transcription factors, the in silico elucidation of Transcription Factor Binding Sites (TFBS) is emerging as an important tool. With this hypothesis, we looked for TFBS over-representation in a PCOS microarray gene set (n=130) using in silico tools. We extracted 1000 bps upstream and 200 bps downstream regions from all these genes and identified 4 different TFBS, which were over-represented as compared to a human promoter background model. These four transcription factors are Staf, E47, CCAAT and CRE-BP1/c-jun. The role of these transcription factors and their compatible members in PCOS pathophysiology is described in details in the text. The factors might provide a novel insight into the pathophysiology of PCOS.