MicroRNAs and ovarian function
TL;DR: The current understanding of miRNA biogenesis, the role and mechanism that miRNAs play in post-transcriptional gene expression regulation, and specifically the current evidence of mi RNA involvement in ovarian development and function are reviewed.
Abstract: MicroRNAs (miRNAs) are a class of small non-coding RNAs which function in gene regulation with an important role in cell proliferation, maturation, and activity. The regulatory role of these small RNA molecules has recently begun to be explored in ovarian cells, uncovering their influence on gonadal development, steroidogenesis, apoptosis, ovulation, and corpus luteum development. This emerging area of research has extended and reshaped our understanding on how ovarian function is regulated. Here, we review the current understanding of miRNA biogenesis, the role and mechanism that miRNAs play in post-transcriptional gene expression regulation, and specifically the current evidence of miRNA involvement in ovarian development and function. Future comprehensive understanding of the role of miRNAs in the ovary in both physiological and pathological conditions may offer new treatment strategies for infertility and other ovarian disorders.
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TL;DR: The presence of exosome or non-exosome mediated transfer of miRNA in the bovine follicular fluid, and oocyte growth dependent variation in extra-cellular miRNA signatures in the follicular environment is demonstrated for the first time.
Abstract: Cell-cell communication within the follicle involves many signaling molecules, and this process may be mediated by secretion and uptake of exosomes that contain several bioactive molecules including extra-cellular miRNAs. Follicular fluid and cells from individual follicles of cattle were grouped based on Brilliant Cresyl Blue (BCB) staining of the corresponding oocytes. Both Exoquick precipitation and differential ultracentrifugation were used to separate the exosome and non-exosomal fraction of follicular fluid. Following miRNA isolation from both fractions, the human miRCURY LNA™ Universal RT miRNA PCR array system was used to profile miRNA expression. This analysis found that miRNAs were present in both exosomal and non-exosomal fraction of bovine follicular fluid. We found 25 miRNAs differentially expressed (16 up and 9 down) in exosomes and 30 miRNAs differentially expressed (21 up and 9 down) in non-exosomal fraction of follicular fluid in comparison of BCB- versus BCB+ oocyte groups. Expression of selected miRNAs was detected in theca, granulosa and cumulus oocyte complex. To further explore the potential roles of these follicular fluid derived extra-cellular miRNAs, the potential target genes were predicted, and functional annotation and pathway analysis revealed most of these pathways are known regulators of follicular development and oocyte growth. In order to validate exosome mediated cell-cell communication within follicular microenvironment, we demonstrated uptake of exosomes and resulting increase of endogenous miRNA level and subsequent alteration of mRNA levels in follicular cells in vitro. This study demonstrates for the first time, the presence of exosome or non-exosome mediated transfer of miRNA in the bovine follicular fluid, and oocyte growth dependent variation in extra-cellular miRNA signatures in the follicular environment.
247 citations
Cites background from "MicroRNAs and ovarian function"
...During the dynamic phase of follicular development and oocyte maturation, miRNAs play an important role by coordinating the expression of genes in a spatial and temporal specific manner [21,22]....
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TL;DR: This study identified a series of exosomal microRNAs that are highly represented in human FF and are involved in follicular maturation and could represent noninvasive biomarkers of oocyte quality in assisted reproductive technology.
178 citations
TL;DR: Serum miRNAs are differentially expressed between PCOS patients and controls, and bioinformatics analysis indicated that the predicted targets function of the three miRN as mainly involved in the metastasis, cell cycle, apoptosis and endocrine.
Abstract: Background: Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women of reproductive age, is characterized by polycystic ovaries, chronic anovulation, hyperandrogenism and insulin resistance. Despite the high prevalence of hyperandrogenemia, a definitive endocrine marker for PCOS has so far not been identified. Circulating miRNAs have recently been shown to serve as diagnostic/prognostic biomarkers in patients with cancers. Our current study focused on the altered expression of serum miRNAs and their correlation with PCOS. Method and Results: We systematically used the TaqMan Low Density Array followed by individual quantitative reverse transcription polymerase chain reaction assays to identify and validate the expression of serum miRNAs of PCOS patients. The expression levels of three miRNAs (miR-222, miR-146a and miR-30c) were significantly increased in PCOS patients with respect to the controls in our discovery evaluation and followed validation. The area under the receiver operating characteristic (ROC) curve (AUC) is 0.799, 0.706, and 0.688, respectively. The combination of the three miRNAs using multiple logistic regression analysis showed a larger AUC (0.852) that was more efficient for the diagnosis of PCOS. In addition, logistic binary regression analyses show miR-222 is positively associated with serum insulin, while miR-146a is negatively associated with serum testosterone. Furthermore, bioinformatics analysis indicated that the predicted targets function of the three miRNAs mainly involved in the metastasis, cell cycle, apoptosis and endocrine. Conclusion: Serum miRNAs are differentially expressed between PCOS patients and controls. We identified and validated a class of three serum miRNAs that could act as novel non-invasive biomarkers for diagnosis of PCOS. These miRNAs may be involved in the pathogenesis of PCOS.
110 citations
TL;DR: It is demonstrated that miR‐133b down‐regulates Foxl2 expression in granulosa cells by directly targeting the 3′UTR, thus inhibiting the Foxl 2‐mediated transcriptional repression of StAR and CYP19A1 to promote estradiol production.
101 citations
Cites background from "MicroRNAs and ovarian function"
...The effects of miRNAs on ovarian function primarily occur through their actions on somatic cells, such as granulosa cells [12]....
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TL;DR: This review considers recent advances in the identification of miRNAs involved in the regulation of ovarian function as well as the possible influence ofmiRNAs on ovarian-derived disorders, such as ovarian cancer, polycystic ovarian syndrome and premature ovarian failure.
Abstract: MicroRNAs (miRNAs) are endogenous, small, noncoding single-stranded RNA molecules approximately 22 nucleotides in length. miRNAs are involved in the post-transcriptional regulation of various important cellular physiological and pathological processes, including cell proliferation, differentiation, apoptosis, and hormone biosynthesis and secretion. Ovarian follicles are the key functional units of female reproduction, and the development of these follicles is a complex and precise process accompanied by oocyte maturation as well as surrounding granulosa cell proliferation and differentiation. Numerous miRNAs expressed in the ovary regulate ovarian follicle growth, atresia, ovulation and steroidogenesis and play an important role in ovarian disorders. This review considers recent advances in the identification of miRNAs involved in the regulation of ovarian function as well as the possible influence of miRNAs on ovarian-derived disorders, such as ovarian cancer, polycystic ovarian syndrome and premature ovarian failure. An improved understanding of the regulation of ovarian function by miRNAs may shed light on new strategies for ovarian biology and ovarian disorders.
97 citations
Cites background from "MicroRNAs and ovarian function"
...Folliculogenesis and steroidogenesis are complex processes involving intraovarian gene expression, signaling pathways, and endocrine and paracrine factors [8, 9]....
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...In each stage of follicle development, different growth factors contribute to stage-specific functions in different cell types [8, 9]....
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References
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TL;DR: The results reveal a role for endogenous siRNAs in mammalian oocytes and show that organisms lacking RdRP activity can produce functional endogenous si RNAs from naturally occurring dsRNAs.
Abstract: RNA interference (RNAi) is a mechanism by which double-stranded RNAs (dsRNAs) suppress specific transcripts in a sequence-dependent manner. dsRNAs are processed by Dicer to 21-24-nucleotide small interfering RNAs (siRNAs) and then incorporated into the argonaute (Ago) proteins. Gene regulation by endogenous siRNAs has been observed only in organisms possessing RNA-dependent RNA polymerase (RdRP). In mammals, where no RdRP activity has been found, biogenesis and function of endogenous siRNAs remain largely unknown. Here we show, using mouse oocytes, that endogenous siRNAs are derived from naturally occurring dsRNAs and have roles in the regulation of gene expression. By means of deep sequencing, we identify a large number of both approximately 25-27-nucleotide Piwi-interacting RNAs (piRNAs) and approximately 21-nucleotide siRNAs corresponding to messenger RNAs or retrotransposons in growing oocytes. piRNAs are bound to Mili and have a role in the regulation of retrotransposons. siRNAs are exclusively mapped to retrotransposons or other genomic regions that produce transcripts capable of forming dsRNA structures. Inverted repeat structures, bidirectional transcription and antisense transcripts from various loci are sources of the dsRNAs. Some precursor transcripts of siRNAs are derived from expressed pseudogenes, indicating that one role of pseudogenes is to adjust the level of the founding source mRNA through RNAi. Loss of Dicer or Ago2 results in decreased levels of siRNAs and increased levels of retrotransposon and protein-coding transcripts complementary to the siRNAs. Thus, the RNAi pathway regulates both protein-coding transcripts and retrotransposons in mouse oocytes. Our results reveal a role for endogenous siRNAs in mammalian oocytes and show that organisms lacking RdRP activity can produce functional endogenous siRNAs from naturally occurring dsRNAs.
1,122 citations
"MicroRNAs and ovarian function" refers background in this paper
...In this regulatory system, endogenous double stranded RNAs (dsRNAs) are thought to derive from pseudogenes that encode a complementary mRNA allowing for formation of dsRNA templates, Dicer cleavage of the dsRNA then generates endogenous siRNAs [36,37]....
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...Endogenous siRNA utilize the well-known RNA interference pathway to regulate gene expression [36,37]....
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...With respect to endogenous siRNAs, they have been identified to play a role in oocytes [36,37]....
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TL;DR: It is reported that a large set of genes involved in basic cellular processes avoid microRNA regulation due to short 3'UTRs that are specifically depleted of microRNA binding sites, ensuring tissue identity and supporting cell-lineage decisions.
1,119 citations
"MicroRNAs and ovarian function" refers background in this paper
...Many highly regulated mRNAs contain multiple miRNA binding sites, often targeted by different miRNAs, which may enhance the effectiveness of regulation [17]....
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TL;DR: These findings indicate a function for pseudogenes in regulating gene expression by means of the RNA interference pathway and may, in part, explain the evolutionary pressure to conserve argonaute-mediated catalysis in mammals.
Abstract: Over evolutionary time, many genes undergo duplication and one copy accumulates mutations that render it non-functional. These 'pseudogenes' are generally thought to be rather uninteresting, dead-end pieces of the genome. Yet there now appears to be more to it than that. Two groups report in this issue on pseudogenes that can in fact influence gene expression. The mechanism involves pairing of RNA antisense transcripts from pseudogenes with the mRNAs of protein-coding genes, forming a duplex RNA that is processed into endogenous siRNAs. Over evolutionary time genes can undergo duplication, and may accumulate mutations that render them non-functional pseudogenes, which are thought to be uninteresting. This study (and that of the group of Sasaki) shows that pseudogenes can in fact influence gene expression. Pseudogenes populate the mammalian genome as remnants of artefactual incorporation of coding messenger RNAs into transposon pathways1. Here we show that a subset of pseudogenes generates endogenous small interfering RNAs (endo-siRNAs) in mouse oocytes. These endo-siRNAs are often processed from double-stranded RNAs formed by hybridization of spliced transcripts from protein-coding genes to antisense transcripts from homologous pseudogenes. An inverted repeat pseudogene can also generate abundant small RNAs directly. A second class of endo-siRNAs may enforce repression of mobile genetic elements, acting together with Piwi-interacting RNAs. Loss of Dicer, a protein integral to small RNA production, increases expression of endo-siRNA targets, demonstrating their regulatory activity. Our findings indicate a function for pseudogenes in regulating gene expression by means of the RNA interference pathway and may, in part, explain the evolutionary pressure to conserve argonaute-mediated catalysis in mammals.
1,059 citations
"MicroRNAs and ovarian function" refers background in this paper
...In this regulatory system, endogenous double stranded RNAs (dsRNAs) are thought to derive from pseudogenes that encode a complementary mRNA allowing for formation of dsRNA templates, Dicer cleavage of the dsRNA then generates endogenous siRNAs [36,37]....
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...Endogenous siRNA utilize the well-known RNA interference pathway to regulate gene expression [36,37]....
[...]
...With respect to endogenous siRNAs, they have been identified to play a role in oocytes [36,37]....
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TL;DR: It is indicated that miRNAs function in the silencing of ES cell self-renewal that normally occurs with the induction of differentiation, and Dicer has miRNA-independent roles in ES cell function.
Abstract: The molecular controls that govern the differentiation of embryonic stem (ES) cells remain poorly understood. DGCR8 is an RNA-binding protein that assists the RNase III enzyme Drosha in the processing of microRNAs (miRNAs), a subclass of small RNAs. Here we study the role of miRNAs in ES cell differentiation by generating a Dgcr8 knockout model. Analysis of mouse knockout ES cells shows that DGCR8 is essential for biogenesis of miRNAs. On the induction of differentiation, DGCR8-deficient ES cells do not fully downregulate pluripotency markers and retain the ability to produce ES cell colonies; however, they do express some markers of differentiation. This phenotype differs from that reported for Dicer1 knockout cells, suggesting that Dicer has miRNA-independent roles in ES cell function. Our findings indicate that miRNAs function in the silencing of ES cell self-renewal that normally occurs with the induction of differentiation.
1,027 citations
TL;DR: The effectiveness of miRNAs as biomarkers for tracing the tissue of origin of cancers of unknown primary origin is demonstrated and the utility of the miRNA biomarkers by quantitative RT-PCR is validated.
Abstract: MicroRNAs (miRNAs) belong to a class of noncoding, regulatory RNAs that is involved in oncogenesis and shows remarkable tissue specificity. Their potential for tumor classification suggests they may be used in identifying the tissue in which cancers of unknown primary origin arose, a major clinical problem. We measured miRNA expression levels in 400 paraffin-embedded and fresh-frozen samples from 22 different tumor tissues and metastases. We used miRNA microarray data of 253 samples to construct a transparent classifier based on 48 miRNAs. Two-thirds of samples were classified with high confidence, with accuracy >90%. In an independent blinded test-set of 83 samples, overall high-confidence accuracy reached 89%. Classification accuracy reached 100% for most tissue classes, including 131 metastatic samples. We further validated the utility of the miRNA biomarkers by quantitative RT-PCR using 65 additional blinded test samples. Our findings demonstrate the effectiveness of miRNAs as biomarkers for tracing the tissue of origin of cancers of unknown primary origin.
967 citations
"MicroRNAs and ovarian function" refers background in this paper
...Recent studies have identified miRNAs as potential tissue specific biomarkers of disease and may provide a useful measure in the diagnosis of numerous pathologies [57]....
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