Sirvi Autor "Altmäe, Signe" järgi

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A speculative outlook on embryonic aneuploidy: Can molecular pathways be involved?
(2018) Tšuiko, Olga; Jatsenko, Tatjana; Parameswaran Grace, Lalit Kumar; Kurg, Ants; Vermeesch, Joris Robert; Lanner, Fredrik; Altmäe, Signe; Salumets, Andres
The journey of embryonic development starts at oocyte fertilization, which triggers a complex cascade of events and cellular pathways that guide early embryogenesis. Recent technological advances have greatly expanded our knowledge of cleavage-stage embryo development, which is characterized by an increased rate of whole-chromosome losses and gains, mixoploidy, and atypical cleavage morphokinetics. Embryonic aneuploidy significantly contributes to implantation failure, spontaneous miscarriage, stillbirth or congenital birth defects in both natural and assisted human reproduction. Essentially, early embryo development is strongly determined by maternal factors. Owing to considerable limitations associated with human oocyte and embryo research, the use of animal models is inevitable. However, cellular and molecular mechanisms driving the error-prone early stages of development are still poorly described. In this review, we describe known events that lead to aneuploidy in mammalian oocytes and preimplantation embryos. As the processes of oocyte and embryo development are rigorously regulated by multiple signal-transduction pathways, we explore the putative role of signaling pathways in genomic integrity maintenance. Based on the existing evidence from human and animal data, we investigate whether critical early developmental pathways, like Wnt, Hippo and MAPK, together with distinct DNA damage response and DNA repair pathways can be associated with embryo genomic instability, a question that has, so far, remained largely unexplored.
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A Two-Cohort RNA-seq Study Reveals Changes in Endometrial and Blood miRNome in Fertile and Infertile Women
(2018) Rekker, Kadri; Altmäe, Signe; Suhorutshenko, Marina; Peters, Maire; Martinez-Blanch, Juan F.; Codoñer, Francisco M.; Vilella, Felipe; Simón, Carlos; Salumets, Andres; Velthut-Meikas, Agne
The endometrium undergoes extensive changes to prepare for embryo implantation and microRNAs (miRNAs) have been described as playing a significant role in the regulation of endometrial receptivity. However, there is no consensus about the miRNAs involved in mid-secretory endometrial functions. We analysed the complete endometrial miRNome from early secretory (pre-receptive) and mid-secretory (receptive) phases from fertile women and from patients with recurrent implantation failure (RIF) to reveal differentially expressed (DE) miRNAs in the mid-secretory endometrium. Furthermore, we investigated whether the overall changes during early to mid-secretory phase transition and with RIF condition could be reflected in blood miRNA profiles. In total, 116 endometrial and 114 matched blood samples collected from two different population cohorts were subjected to small RNA sequencing. Among fertile women, 91 DE miRNAs were identified in the mid-secretory vs. early secretory endometrium, while no differences were found in the corresponding blood samples. The comparison of mid-secretory phase samples between fertile and infertile women revealed 21 DE miRNAs from the endometrium and one from blood samples. Among discovered novel miRNAs, chr2_4401 was validated and showed up-regulation in the mid-secretory endometrium. Besides novel findings, we confirmed the involvement of miR-30 and miR-200 family members in mid-secretory endometrial functions.
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Endometrial receptivity revisited: endometrial transcriptome adjusted for tissue cellular heterogeneity
(2018) Suhorutshenko, Marina; Kukushkina, Viktorija; Velthut-Meikas, Agne; Altmäe, Signe; Peters, Maire; Mägi, Reedik; Krjutškov, Kaarel; Koel, Mariann; Codoñer, Francisco M; Martinez-Blanch, Juan Fco; Vilella, Felipe; Simón, Carlos; Salumets, Andres; Laisk, Triin
STUDY QUESTION Does cellular composition of the endometrial biopsy affect the gene expression profile of endometrial whole-tissue samples? SUMMARY ANSWER The differences in epithelial and stromal cell proportions in endometrial biopsies modify the whole-tissue gene expression profiles and affect the results of differential expression analyses. WHAT IS ALREADY KNOWN Each cell type has its unique gene expression profile. The proportions of epithelial and stromal cells vary in endometrial tissue during the menstrual cycle, along with individual and technical variation due to the method and tools used to obtain the tissue biopsy. STUDY DESIGN, SIZE, DURATION Using cell-population specific transcriptome data and computational deconvolution approach, we estimated the epithelial and stromal cell proportions in whole-tissue biopsies taken during early secretory and mid-secretory phases. The estimated cellular proportions were used as covariates in whole-tissue differential gene expression analysis. Endometrial transcriptomes before and after deconvolution were compared and analysed in biological context. PARTICIPANTS/MATERIAL, SETTING, METHODS Paired early- and mid-secretory endometrial biopsies were obtained from 35 healthy, regularly cycling, fertile volunteers, aged 23–36 years, and analysed by RNA sequencing. Differential gene expression analysis was performed using two approaches. In one of them, computational deconvolution was applied as an intermediate step to adjust for the proportions of epithelial and stromal cells in the endometrial biopsy. The results were then compared to conventional differential expression analysis. Ten paired endometrial samples were analysed with qPCR to validate the results. MAIN RESULTS AND THE ROLE OF CHANCE The estimated average proportions of stromal and epithelial cells in early secretory phase were 65% and 35%, and during mid-secretory phase, 46% and 54%, respectively, correlating well with the results of histological evaluation (r = 0.88, P = 1.1 × 10−6). Endometrial tissue transcriptomic analysis showed that approximately 26% of transcripts (n = 946) differentially expressed in receptive endometrium in cell-type unadjusted analysis also remain differentially expressed after adjustment for biopsy cellular composition. However, the other 74% (n = 2645) become statistically non-significant after adjustment for biopsy cellular composition, underlining the impact of tissue heterogeneity on differential expression analysis. The results suggest new mechanisms involved in endometrial maturation, involving genes like LINC01320, SLC8A1 and GGTA1P, described for the first time in context of endometrial receptivity. LARGE-SCALE DATA The RNA-seq data presented in this study is deposited in the Gene Expression Omnibus database with accession number GSE98386. LIMITATIONS REASONS FOR CAUTION Only dominant endometrial cell types were considered in gene expression profile deconvolution; however, other less frequent endometrial cell types also contribute to the whole-tissue gene expression profile. WIDER IMPLICATIONS OF THE FINDINGS The better understanding of molecular processes during transition from pre-receptive to receptive endometrium serves to improve the effectiveness and personalization of assisted reproduction protocols. Biopsy cellular composition should be taken into account in future endometrial ‘omics’ studies, where tissue heterogeneity could potentially influence the results. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by: Estonian Ministry of Education and Research (grant IUT34-16); Enterprise Estonia (EU48695); the EU-FP7 Eurostars program (NOTED, EU41564); the EU-FP7 Marie Curie Industry-Academia Partnerships and Pathways (SARM, EU324509); Horizon 2020 innovation program (WIDENLIFE, EU692065); MSCA-RISE-2015 project MOMENDO (No 691058) and the Miguel Servet Program Type I of Instituto de Salud Carlos III (CP13/00038); Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER): grants RYC-2016-21199 and ENDORE SAF2017-87526. Authors confirm no competing interests.
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Genomics and transcriptomics of human induced ovarian folliculogenesis
(2010-01-08T05:57:20Z) Altmäe, Signe
Infertility is an increasing medical and social problem affecting more than 10% of couples of their fertile age. In Estonia, accordingly, more than 15 000 infertile couples could be suspected. In vitro fertilization (IVF) procedure is the most successful treatment for various causes of infertility. Regardless of constant improvement of pregnancy rate in IVF, the success rates are still around 30% per cycle. IVF procedure consists of three steps – the stimulation of the ovaries (called controlled ovarian hyperstimulation (COH)), fertilisation of the retrieved oocytes and culturing of embryos, and finally the embryo transfer. The expected outcome of the IVF treatment depends greatly on the effectiveness of COH, where follicle-stimulating horomone (FSH) is used to induce the (poly)folliculogenesis, as well as on the quality of oocytes. Sufficient number of mature oocytes is crucial for high pregnancy rates, compensating possible losses during follicular puncture, fertilization, embryo development and implantation, meanwhile hormone overdoses can lead to the life-threatening conditions known as ovarian hyper-stimulation syndrome (OHSS). The response to the FSH stimulation varies substantially among individuals and is difficult to predict. Several markers have been proposed, but the search for optimal markers that could predict COH outcome and also a good-quality oocyte, enabling thereby better IVF treatment outcome, is ongoing. In the current thesis we studied polymorphisms in genes involved in folliculogenesis – aromatase gene, estrogen receptor genes and genes involved in folate metabolism, and their influence on COH and IVF outcome in women undergoing IVF procedure. Also the importance of different polymorphisms in the etiology of female infertility was assessed. In addition, in order to add more understanding to the field of follicular biology in IVF treatment, gene expression profiles of mural granulosa cells and cumulus granulosa cells were analysed. The results of the current thesis demonstrate that the genetic variation in genes involved in folliculogenesis influences the stimulatory effect of FSH used in ovarian stimulation in IVF patients and are associated with etiology of female infertility. The knowledge of the individual’s genetic background would enable to predict the FSH doses needed for optimal ovarian stimulation in IVF treatment in order to avoid the poor response or hyper-response to the hormonal ovarian stimulation. Further, the data of the granulosa cell gene expression add information to the process of hormonal stimulation in IVF, which could be applied in improving IVF treatment protocols and embryo selection. These findings, together with previous studies have great importance for future development in infertility treatment, allowing to individualise the patient’s COH protocols and to make thereby IVF procedure safer and more effective.
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Stanniocalcin-1 expression in normal human endometrium and dysregulation in endometriosis
(2016) Aghajanova, Lusine; Altmäe, Signe; Kasvandik, Sergo; Salumets, Andres; Stavreus-Evers, Anneli; Giudice, Linda C.
Objective To determine expression of stanniocalcin-1 (STC1) in human endometrium with and without endometriosis and its regulation by steroid hormones. Design Laboratory study. Setting University. Patient(s) Nineteen women with endometriosis and 33 control women. Intervention(s) Endometrial biopsy and fluid sampling. Main Outcome Measure(s) Analysis of early secretory (ESE) and midsecretory (MSE) endometrial secretomes from fertile women with the use of nano–liquid chromatography–dual mass spectrometry; real-time quantitative polymerase chain reaction, and immunohistochemistry for STC1 and its receptor calcium-sensing receptor (CASR) mRNA and proteins in endometrium with and without endometriosis; evaluation of STC1 and CASR mRNA expression in endometrial stromal fibroblasts (eSF) from women with and without endometriosis decidualized with the use of E2P or 8-bromo-cyclic adenosine monophosphate (cAMP). Result(s) STC1 protein was strongly up-regulated in MSE versus ESE in endometrial fluid of fertile women. STC1 mRNA significantly increased in MSE from women with, but not from those without, endometriosis, compared with proliferative endometrium or ESE, with no significant difference throughout the menstrual cycle between groups. STC1 mRNA in eSF from control women increased >230-fold on decidualization with the use of cAMP versus 45-fold from women with endometriosis, which was not seen on decidualization with E2/P. CASR mRNA did not exhibit significant differences in any condition and was not expressed in isolated eSF. STC1 protein immunoexpression in eSF was significantly lower in women with endometriosis compared with control women. Conclusion(s) STC1 protein is significantly up-regulated in MSE endometrial fluid and is dysregulated in eutopic endometrial tissue from women with endometriosis. It is likely regulated by cAMP and may be involved in the pathogenesis of decidualization defects.