Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human endrometrium samples obtained across the menstrual cycle of normo-ovulatory women to determine molecular signatures for different phases

ABSTRACT: To examine the possibility that biochemical,or molecular signatures of endometrium may prove to be more useful, we have investigated,whole genome molecular phenotyping (54,600 genes/ESTs) of this tissue sampled across the,cycle in 28 normo-ovulatory women, using high-density oligonucleotide microarrays. The results demonstrate,that endometrial samples obtained by two different sampling techniques (biopsy and curetting,hysterectomy specimens) from subjects who are as normal as possible in a human study and,4,including those with unknown histology, can be classified by their molecular signatures and,correspond to known phases of the menstrual cycle with identical results using two independent,analytical methods. Also, the results enable global identification of biological processes and,molecular mechanisms that occur dynamically in the endometrium in the changing steroid,hormone milieu across the menstrual cycle in normo-ovulatory women. The results underscore,the potential of gene expression profiling for developing molecular diagnostics of endometrial,normalcy and abnormalities and identifying molecular targets for therapeutic purposes in,endometrial disorders.

ORGANISM(S): Homo sapiens

SUBMITTER: Talbi Said

PROVIDER: E-GEOD-4888 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women.

Talbi S S Hamilton A E AE Vo K C KC Tulac S S Overgaard M T MT Dosiou C C Le Shay N N Nezhat C N CN Kempson R R Lessey B A BA Nayak N R NR Giudice L C LC

Endocrinology 20051123 3

Histological evaluation of endometrium has been the gold standard for clinical diagnosis and management of women with endometrial disorders. However, several recent studies have questioned the accuracy and utility of such evaluation, mainly because of significant intra- and interobserver variations in histological interpretation. To examine the possibility that biochemical or molecular signatures of endometrium may prove to be more useful, we have investigated whole-genome molecular phenotyping ...[more]

PMID: 16306079

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Project description:Abstract: Objective: Adenomyosis is a clinical disorder defined by the presence of endometrial glands and stroma within the myometrium, the pathogenesis of which is poorly understood. We postulate that dysregulation of genes and pathways in eutopic endometrium may predispose to ectopic implantation. No study, to our knowledge, has examined the global transcriptome of isolated eutopic endometrium from women with clinically significant adenomyosis. Design: Laboratory-based study with full IRB approval and consents. Material and Methods: Endometrial sampling was performed on hysterectomy specimens (proliferative phase) from symptomatic women with pathologically-confirmed diffuse adenomyosis (n=3). Controls (n=5) were normo-ovulatory subjects without adenomyosis. All subjects were free from leiomyoma, endometriosis, and hormonal exposures. Isolated purified total RNA was subjected to microarray analysis using the Gene 1.0 ST Affymetrix platform. Data were analyzed with GeneSpring and Ingenuity Pathway analysis. Validation of several genes was undertaken by QRT-PCR. Results: Comparison of transcriptomes of proliferative endometrium from women with and without adenomyosis revealed 140 up-regulated and 884 down-regulated genes in samples from women with adenomyosis compared to controls. Highly differentially expressed genes include those involved in regulation of apoptopsis, steroid hormone responsiveness, and proteins involved in extracellular matrix remodeling, as well as microRNAs of unknown significance. Affected canonical pathways included eukaryotic initiation factor 2 signaling, oxidative phosphorylation, mitochondrial dysfunction, estrogen receptor signaling, and mTOR signaling. Conclusions: The eutopic endometrium in patients with adenomyosis has fundamental abnormalities that may predispose to invasion and survival beyond the myometrial interface. Key Words: adenomyosis, endometrium, microarray, microRNA, endometriosis, apoptosis, signaling. Abstract: Objective: Adenomyosis is a clinical disorder defined by the presence of endometrial glands and stroma within the myometrium, the pathogenesis of which is poorly understood. We postulate that dysregulation of genes and pathways in eutopic endometrium may predispose to ectopic implantation. No study, to our knowledge, has examined the global transcriptome of isolated eutopic endometrium from women with clinically significant adenomyosis. Design: Laboratory-based study with full IRB approval and consents. Material and Methods: Endometrial sampling was performed on hysterectomy specimens (proliferative phase) from symptomatic women with pathologically-confirmed diffuse adenomyosis (n=3). Controls (n=5) were normo-ovulatory subjects without adenomyosis. All subjects were free from leiomyoma, endometriosis, and hormonal exposures. Isolated purified total RNA was subjected to microarray analysis using the Gene 1.0 ST Affymetrix platform. Data were analyzed with GeneSpring and Ingenuity Pathway analysis. Validation of several genes was undertaken by QRT-PCR. Results: Comparison of transcriptomes of proliferative endometrium from women with and without adenomyosis revealed 140 up-regulated and 884 down-regulated genes in samples from women with adenomyosis compared to controls. Highly differentially expressed genes include those involved in regulation of apoptopsis, steroid hormone responsiveness, and proteins involved in extracellular matrix remodeling, as well as microRNAs of unknown significance. Affected canonical pathways included eukaryotic initiation factor 2 signaling, oxidative phosphorylation, mitochondrial dysfunction, estrogen receptor signaling, and mTOR signaling. Conclusions: The eutopic endometrium in patients with adenomyosis has fundamental abnormalities that may predispose to invasion and survival beyond the myometrial interface. Key Words: adenomyosis, endometrium, microarray, microRNA, endometriosis, apoptosis, signaling. A total of 8 samples were used and analyzed by disease state. Endometrial samples from hysterectomy specimens in proliferative phase of menstrual cycle from symptomatic women with pathologically-confirmed diffuse adenomyosis were compared with endometrial samples from normo-ovulatory healthy subjects with no endometrial or uterine pathology.

Project description:Background: a fundamental challenge for reproductive biology is to understand the menstrual cycle, specially the window of implantation, whose regulation and mechanistic remain incompletely understood in human reproductive physiology. Transcriptomics from a systems biology perspective provides a genomic framework to discover endometrial tissue specific regulation and behavior and its function in reproductive physiology. Results: Here, we applied a transcriptomic analysis of 238 endometrial receptivity related genes using a customized Agilent platform. 507 human endometrial biopsies were analyzed among the menstrual cycle, especially in the expected window of implantation and divided in to transcriptomic profiles using machine learning predictors (SVM and KNN models). The clinical relevance of these profiles was tested defining the best transcriptomic profile for pregnancy and live birth. Weighed Gene Co-expression Networks (WGCN) was applied is these clinically well-defined endometrial states to characterize the gene co-expression tissue specific regulation in humans for pregnancy in comparison with the other transcriptomic stages of menstrual cycle. For the first time, the menstrual cycle has been mapped as a percentage of positive and negative correlations between genes. Thanks to this approach, we have discovered the WOI as the fewest negatively correlated state with the highest proportion of positive correlations (Cochran´s Q = 14324.12, FDR < 2.2e-16) with an average of 84% of positive correlations in pregnant profile, while 53% in the two previous Proliferative (PF) and Early Pre-Receptive profiles and 67% in the late secretory endometrium, just before menstruation renewal. Finally, this study provides a wealth of network data to the scientific community to stimulate hypothesis-driven single-molecule endometrial studies in the form of a user-friendly database called the Menstrual Cycle Gene Co-expression Network (website: www.menstrualcyclegcn.com). Conclusions: this genomic research reveals for first time the pregnant endometrium as a global derepressed state in human menstrual cycle. This indicates the endometrium is generally a repressive tissue in human menstrual cycle with a relaxed WOI period where gene expression reaches the highest proportion of positive correlation, indicating that a decrease of inhibition may allow embryo implantation. Detailed molecular information about co-expression among menstrual cycle is also provided.

Dataset Information

Transcription profiling of human endrometrium samples obtained across the menstrual cycle of normo-ovulatory women to determine molecular signatures for different phases

Publications

Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women.

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