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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 1  |  Page : 11-17

The messenger RNA and long non-coding RNA expression profiles in ectopic and eutopic endometrium provide novel insights into endometriosis


1 Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, China
2 Department of Obstetrics and Gynecology, Zhenjiang Maternal and Child Health Hospital, Zhenjiang 212001, China

Date of Submission21-Dec-2018
Date of Web Publication11-Apr-2019

Correspondence Address:
Ke-Qin Hua
Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 Shenyang Road, Shanghai 200090
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.255992

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  Abstract 


Objective: To establish the messenger RNA (mRNA) and long non-coding RNA (lncRNA) expression profiles in ectopic and eutopic endometrium and provide novel insights into endometriosis.
Methods: The mRNA and lncRNA expression profiles were tested using high-throughput sequencing technology in ectopic and eutopic endometrium with endometriosis and normal endometrium without endometriosis. The potential targeted lncRNAs were annotated by analyzing the correlation between lncRNA and mRNA expression to better understand the pathogenesis of endometriosis.
Results: In ectopic compared with normal endometrium, a total of 2,188 mRNAs and 1,200 lncRNAs were differentially expressed with a fold-change (FC) ≥2.5. In eutopic compared with normal endometrium, a total of 2,324 mRNAs and 695 lncRNAs were differentially expressed with an FC ≥1.5. In ectopic compared with eutopic endometrium, a total of 2,223 mRNAs and 511 lncRNAs were differentially expressed with an FC ≥2. Bioinformatic analysis indicated that the differentially expressed mRNAs were enriched in the biological processes and signaling pathways involved in endometriosis. In addition, we constructed a gene coexpression network based on the dysregulated lncRNAs in both ectopic endometrium and eutopic endometrium, combined with their coexpressed mRNAs to simulate the complex interactions.
Conclusions: This study describes the first-to-integrate analysis of the differential expression profiles of mRNAs and lncRNAs, including analyses between ectopic and normal endometrium, eutopic and normal endometrium, and ectopic and eutopic endometrium, which provides new insights to investigate the pathogenesis of endometriosis and explore novel diagnostic biomarkers and therapeutic targets.

Keywords: Endometriosis; Gene Profile; Long Non-coding RNA; Messenger RNA; RNA Sequencing


How to cite this article:
Liu SP, Tian X, Cui HY, Zhang Q, Hua KQ. The messenger RNA and long non-coding RNA expression profiles in ectopic and eutopic endometrium provide novel insights into endometriosis. Reprod Dev Med 2019;3:11-7

How to cite this URL:
Liu SP, Tian X, Cui HY, Zhang Q, Hua KQ. The messenger RNA and long non-coding RNA expression profiles in ectopic and eutopic endometrium provide novel insights into endometriosis. Reprod Dev Med [serial online] 2019 [cited 2019 Apr 24];3:11-7. Available from: http://www.repdevmed.org/text.asp?2019/3/1/11/255992




  Introduction Top


Endometriosis is defined as the presence and growth of endometrial glands and stroma outside the uterine cavity, which mainly involves the pelvic peritoneum, ovaries, and rectovaginal septum. It is associated with dysmenorrhea, chronic pelvic pain, dyspareunia, and infertility and affects 10%–15% of women of reproductive age.[1]

Endometriosis is a benign disorder with malignant biological behaviors, including recurrence and metastasis.[2],[3] The pathogenesis of endometriosis is still not fully understood, and several hypotheses have been proposed to explain the etiology, such as retrograde menstrual reflux, coelomic metaplasia, immune system defects, genetic predisposition, and stem cells.[4],[5],[6],[7],[8],[9] There is growing evidence indicating the involvement of genetic factors in the etiology of endometriosis. A study showed that, compared to the general population, the prevalence of endometriosis in first-degree relatives of women with endometriosis was increased 6–9-fold.[10] Endometriosis-linked genes have been extensively investigated, which revealed some genes that may mediate the initiation and development of endometriosis.[7],[8],[9]

Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs at least 200 nucleotides in length and were originally disregarded in early studies as transcriptional noise because of their low expression levels. However, there is now accumulating evidence, suggesting that lncRNAs function in various biological processes and they can regulate gene expression via transcription, translation, and posttranslational modifications to participate in the pathogenesis of various diseases, including endometriosis.[11],[12],[13]

This study was performed to establish the differential expression profiles of messenger RNA (mRNA) and lncRNA in the eutopic and ectopic endometrium of endometriosis, with the aim of furthering our understanding of the pathogenesis of endometriosis.


  Methods Top


Patients and samples

Three types of endometrium tissues were collected: (1) ovarian endometrioma (ectopic endometrium); (2) endometrium from women with endometriosis (eutopic endometrium, matched samples) (n = 3) was collected from women aged 40–50 years who underwent hysterectomies and ovarian cystectomies through laparoscopy; and (3) endometrium from women without endometriosis (normal endometrium) (n = 3) was collected from women aged 42–50 years who underwent hysterectomies for leiomyoma at the Zhenjiang Maternal and Child Health Hospital, China, from January 2017 to May 2017. All patients had regular menstrual cycles and were in the proliferative phase. The patients also had not taken exogenous hormones for 6 months before surgery. Biopsies of the uterine wall (1 cm full-thickness) were taken for eutopic endometrium and normal endometrium. Harvested samples were divided into two parts: one part was snap-frozen in liquid nitrogen for RNA extraction and the other part was fixed and used for hematoxylin and eosin (HE) staining and pathological examination.

Informed written consent was obtained from each patient, and ethical approval was obtained from the Institutional Review Board of Zhenjiang Maternal and Child Health Hospital (No. 20161204).

RNA-sequencing analysis

LncRNA and mRNA expression analysis was performed in three samples of ectopic endometrium, matched eutopic endometrium, and normal endometrium using the Illumina Sequencing Systems (Illumina, CA, USA).

Sample RNA was isolated using the TRIzol reagent (Invitrogen, CA, USA), and good RNA integrity was confirmed as RIN >7 on a bioanalyzer (Agilent Technologies, CA, USA). Libraries were prepared according to the Total RNA-sequencing (H/M/R) Library Prep Kit (Vazyme Biotech Co., Nanjing, China) protocol. Briefly, RNA was purified to remove rRNA using VAHTSTM RNA Clean Beads. Then, the purified RNA was amplified and transcribed into magnetic bead-labeled cRNA. Libraries were pooled and sequenced on an Illumina Sequencing Systems (Illumina, CA, USA) with 100 bp paired-end reads.

Bioinformatic analysis

After the low-quality reads were removed, the remaining reads were mapped to the human reference genome (version hg19, RefSeq), and the relative expression levels of genes were normalized by reads per kilobase million using cufflinks (version 2.0.2, http://cole-trapnell-lab.github.io/cufflinks/). Differential expression of mRNAs or lncRNAs was displayed as fold-change (FC) with P < 0.05 (unpaired-test). Gene heatmaps were generated to show distinguishable expression patterns of mRNAs or lncRNAs.

All of the raw and processed RNA-sequencing data were analyzed with the gene ontology (GO) database to find upregulated and downregulated genes. From this list, we randomly chose differentially expressed mRNAs and lncRNAs (one each from the upregulated and downregulated list for four genes total) and validated their expression by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The differentiated genes were also analyzed with Kyoto Encyclopedia of Genes and Genomes (KEGG) to identify correlated pathways. The coexpression networks of mRNA and lncRNA were constructed with specific expression levels according to their normalized signal intensities. Fisher's exact and Chi-square tests were performed to analyze the functions and pathways of different genes. Pearson's correlation coefficient was calculated for each pair of genes, and significantly correlated pairs were chosen to construct the network. P < 0.05 was considered statistically significant.


  Results Top


Hematoxylin and eosin staining

Every sample was confirmed by HE staining and pathological examination. Endometriosis was diagnosed when two or more of these four histological elements were observed: endometrial glands, endometrial stroma, fibers, and macrophages rich in hemosiderin [Figure 1]a. Eutopic and normal endometrium contained a few uterine glands, numerous matrix cells, reticular fibers, and blood vessels [Figure 1]b and [Figure 1]c.
Figure 1: HE staining for ectopic endometrium (a), eutopic endometrium (b), and normal endometrium (c) with ×100.

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Differential expression of messenger RNAs and long non-coding RNAs

In ectopic compared with normal endometrium, a total of 2,188 differentially expressed mRNAs and 1,200 lncRNAs were identified by RNA-sequencing analysis (FC ≥2.5, P < 0.05). Of the mRNAs, 971 were upregulated and 1,217 were downregulated. Of the lncRNAs, 481 were upregulated and 719 were downregulated [Figure 2]a and [Figure 2]b.
Figure 2: Hierarchical clustering heatmap of differentially expressed mRNAs (a) and lncRNAs (b) in the ectopic endometrium compared with the normal endometrium. Red: Higher expression levels; Green: Lower expression levels. mRNAs: Messenger RNAs; lncRNAs: Long non-coding RNAs.

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In eutopic compared with normal endometrium, a total of 2,324 mRNAs and 695 lncRNAs were identified by RNA-sequencing analysis (FC ≥1.5, P < 0.05). Of the mRNAs, 1,101 were upregulated and 1,223 were downregulated. Of the lncRNAs, 368 were upregulated and 327 were downregulated [Figure 3]a and [Figure 3]b.
Figure 3: Hierarchical clustering heatmap of differentially expressed mRNAs (a) and lncRNAs (b) in the eutopic endometrium compared with the normal endometrium. Red: Higher expression levels; Green: Lower expression levels. mRNAs: Messenger RNAs; lncRNAs: Long non-coding RNAs.

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In ectopic compared with eutopic endometrium, a total of 2,223 mRNAs and 511 lncRNAs were identified by RNA-sequencing analysis (FC ≥2, P < 0.05). Of the mRNAs, 1,221 were upregulated and 1,002 were downregulated. Of the lncRNAs, 191 were upregulated and 320 were downregulated [Figure 4]a and [Figure 4]b.
Figure 4: Hierarchical clustering heatmap of differentially expressed mRNAs (a) and lncRNAs (b) in the ectopic endometrium compared with the eutopic endometrium. Red: Higher expression levels; Green: Lower expression levels. mRNAs: Messenger RNAs; lncRNAs: Long non-coding RNAs.

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Validation by quantitative reverse transcription polymerase chain reaction

To confirm the sequencing and bioinformatic results, ectopic and eutopic endometrium samples were obtained from 15 patients with endometriosis aged 24–51 years and normal endometrium samples were obtained from 15 participants aged 25–49 years without endometriosis from June 2017 to December 2017, and one upregulated and one downregulated mRNA (ICAM1 and MIR199A2, respectively) and one upregulated and one downregulated lncRNA (PRKAR2B and CLEC2D, respectively) were chosen randomly from the list of differentially expressed lncRNAs and mRNAs to validate by qRT-PCR. They were found to be differentially expressed in the samples with the same trends [P < 0.05, [Figure 5], which was consistent with sequencing results.
Figure 5: qRT-PCR validation of the expression of two randomly chosen mRNAs and lncRNAs. Relative gene expression FC measured by qRT-PCR (light gray bars) was consistent with the sequencing results (dark gray bars) between ectopic and normal endometrium (a), eutopic and normal endometrium (b), and ectopic and eutopic endometrium (c). qRT-PCR: Quantitative reverse transcription polymerase chain reaction; mRNAs: Messenger RNAs; lncRNAs: Long non-coding RNAs; FC: Fold-change.

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Gene ontology and pathway analysis

In ectopic compared with normal endometrium, genes with an FC ≥2.5 underwent GO analysis. The upregulated genes were found to be involved in a variety of pathways including cell adhesion, innate immune response, blood coagulation, inflammatory response, cellular response to follicle-stimulating hormone stimulus, cell migration, and estrogen biosynthetic process. By contrast, the downregulated genes were involved in the apoptotic process and cytokinesis [Figure 6]a and [Figure 6]b.
Figure 6: Bioinformatic analysis of differentially expressed mRNAs in ectopic endometrium compared with normal endometrium. (a) GO analysis of upregulated mRNAs. (b) GO analysis of downregulated mRNAs. (c) Top pathway annotations of upregulated mRNAs. (d) Top pathway annotations of downregulated mRNAs. mRNAs: Messenger RNAs; GO: Gene ontology.

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The major pathways thought to involve upregulated mRNAs in ectopic versus normal endometrium included the coagulation cascades, transforming growth factor β (TGFβ) signaling pathway, PI3K-Akt signaling pathway, focal adhesions, ovarian steroidogenesis, mitogen-activated protein kinase (MAPK) signaling pathway, and steroid hormone biosynthesis. Meanwhile, downregulated mRNAs in ectopic versus normal endometrium were predicted to be involved in pathways of estrogen signaling and cell adhesion molecules [Figure 6]c and [Figure 6]d.

In eutopic compared with normal endometrium, genes with an FC ≥1.5 underwent GO analysis. These upregulated genes were found to be involved in a variety of pathways including inflammatory response, negative regulation of the apoptotic process, angiogenesis, positive regulation of nuclear factor-kappa B (NF-κB) transcription factor activity, blood coagulation, positive regulation of cell proliferation, and innate immune response. By contrast, the downregulated genes were involved in immune response pathways, positive regulation of Jun N-terminal kinase cascade, chemokine secretion, and interleukin-10 secretion [Supplementary Figure 1]a and [Supplementary Figure 1]b. [Additional file 1]

The major pathways thought to involve upregulated mRNAs in eutopic versus normal endometrium included cytokine–cytokine receptor interaction, hypoxia-inducible factor-1 signaling, MAPK signaling, apoptosis, PI3K-Akt signaling, just another kinase-signal transducer and activator of transcription signaling, NF-κB signaling, and focal adhesions. Meanwhile, downregulated mRNAs in eutopic versus normal endometrium were predicted to be involved in pathways of the ribosome function [Supplementary Figure 1]c and [Supplementary Figure 1]d.

We also performed GO analysis on genes with an FC ≥2 that were common between ectopic and eutopic endometrium compared with normal endometrium. The upregulated genes were found to be involved in a variety of pathways including platelet degranulation, angiogenesis, cell adhesion, blood coagulation, positive regulation of cell migration, immune response, platelet activation, negative regulation of apoptotic process, and cytokine-mediated signaling. By contrast, the downregulated genes were involved in platelet development, positive regulation of apoptotic process, and negative regulation of cell–cell adhesion [Supplementary Figure 2]a and [Supplementary Figure 2]b.

For the mRNAs common between ectopic and eutopic endometrium compared with normal endometrium, the major pathways predicted to involve the upregulated mRNAs included coagulation cascades, focal adhesions, the PI3K-Akt signaling pathway, cell adhesion molecules, the NF-κB signaling pathway, cytokine–cytokine receptor interactions, and ovarian steroidogenesis. Meanwhile, the downregulated mRNAs were predicted to be involved in pathways in cancer [Supplementary Figure 2]c and [Supplementary Figure 2]d. [Additional file 2]

Genes with an FC ≥2 in ectopic compared with eutopic endometrium underwent GO analysis. The upregulated genes were found to be involved in a variety of pathways including cell proliferation and the apoptotic process, whereas the downregulated genes were also involved in the apoptotic process [Supplementary Figure 3]a and [Supplementary Figure 3]b.

The major pathways thought to involve the upregulated mRNAs in ectopic versus eutopic endometrium included pathways in cancer and MAPK signaling, whereas the downregulated mRNAs were thought to be involved in pathways of coagulation cascades, focal adhesions, PI3K-Akt signaling, TGFβ signaling, and MAPK signaling [Supplementary Figure 3]c and [Supplementary Figure 3]d. [Additional file 3]

Coexpression profiles of long non-coding RNA and messenger RNA and long non-coding RNA function prediction

Of the differentially expressed genes when comparing ectopic and normal endometrium, 132 lncRNAs and 322 mRNAs were also differentially expressed when comparing eutopic and normal endometrium. A coexpression network was constructed to explore the correlation and interaction between these common lncRNAs and mRNAs. The network consisted of dysregulated lncRNAs and their trans-target mRNAs [Figure 7]. These identified candidate lncRNAs may interact with these mRNAs and play important roles in the pathogenesis of endometriosis.
Figure 7: lncRNA-mRNA correlation network. The interaction network of differentially expressed genes (Signal-net). Filled circles represent mRNA and open circles represent lncRNA (red: upregulated genes; blue: downregulated genes). Solid line represents positive regulation and dotted line represents negative regulation. mRNA: Messenger RNA; lncRNA: Long non-coding RNA.

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  Discussion Top


In recent years, the functions of lncRNAs in the pathogenesis of gynecological diseases have gained a lot of attention.[14],[15] Research has similarly focused on the role of lncRNAs in the pathogenesis of endometriosis, and the endometriosis-related mRNA and lncRNA expression profiles have been evaluated as a new tool for the possible diagnosis of endometriosis.[11],[12],[13]

However, most of these previous studies focused on the differences of mRNA and lncRNA profiles only between eutopic and normal endometrium, or between eutopic and ectopic endometrium, thus failing to provide an overall identification among ectopic, eutopic, and normal endometrium.[16],[17] To the best of our knowledge, this study is the first-to-integrate analysis of the differential expression profiles of mRNAs and lncRNAs during the proliferative phase of endometriosis, which included analyses between ectopic and normal endometrium, eutopic and normal endometrium, and ectopic and eutopic endometrium.

The expression profiles of mRNAs and lncRNAs in endometriosis were reported differently in the previous literature. Cui et al. determined the lncRNA and mRNA expression patterns in eutopic endometrium and normal endometrium during the proliferative phase using RNA-sequencing and found 86 dysregulated lncRNAs and 1,228 dysregulated mRNAs.[16] Sun et al. investigated ectopic and eutopic endometrial lncRNA and mRNA expression levels by microarray in four patients and found that a total of 948 lncRNAs and 4,088 mRNAs were dysregulated in ectopic endometrial tissue, compared with paired eutopic endometrial tissue.[17] In the present study, high-throughput RNA-sequencing showed that 2,188 mRNAs and 1,200 lncRNAs were dysregulated in the ectopic endometrium of endometriosis patients compared with the normal endometrium, 2,223 mRNAs and 511 lncRNAs in the eutopic endometrium of endometriosis patients compared with the normal endometrium, and 2,223 mRNAs and 511 lncRNAs in the ectopic endometrium of endometriosis patients compared with the matched eutopic endometrium. Variations in the differentially expressed lncRNAs and mRNAs were identified in our study and the previous studies that can be explained by a couple reasons. First, endometriosis is an estrogen-dependent disorder and the molecular phenotype of the endometrium varies with the menstrual cycle,[18] which causes the gene profiles to vary with the phase of the tissue sample collection. Second, the gene profile results also depend on the FC selected during the process of data analysis. Third, all of the studies had small sample sizes and the results needed to be further verified by larger samples.

Although gene chip and high-throughput sequencing technologies have been widely used in recent years, lncRNA research is still at the primary stage and the exact function of many lncRNAs remains unclear.[19] At present, lncRNA sequences are usually investigated with mRNA, and lncRNAs can be annotated by analyzing the correlation between lncRNA and mRNA expression based on the results of GO and KEGG analysis of mRNAs. It is known that the pathogenesis of endometriosis is multifactorial, and studies have revealed gene expression differences between the ectopic and eutopic endometrium of women with or without endometriosis.[7],[8],[9]

According to GO analysis results in the present study, the different genes were involved in pathways of angiogenesis, cell adhesion, cell migration, immune response, inflammatory response, NF-κB signaling pathway, etc., which have been recognized for involvement in the development of endometriosis.[20],[21] Another example, in this study, the enrichment of some mRNAs in the innate immune response indicated a correlation between immune factors and endometriosis, which has been confirmed in some prior studies. Data summarized in a study showed that macrophages residing inside the peritoneal cavity were the most relevant immunocytes for endometriosis,[22] furthermore, the ratios of Th1 to Th2 cells, the production of cytokines and chemoattractants were imbalanced in endometriosis.[22] However, it was not clear if they were contributing factors or results of endometriosis.

It was worth noting that this study also obtained some findings which were reported rarely in the previous literature. Some mRNAs were found to be enriched in the biological process of blood coagulation. Lin et al. found that the levels of plasma prothrombin time and thrombin time in patients with ovarian endometriosis were significantly shorter than those with benign ovarian cysts, whereas the levels of plasma fibrinogen, D-dimer, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were significantly higher than the control.[23] These data suggested that the abnormality of coagulation may be involved in the pathogenesis of ovarian endometriosis. In addition, this study showed that some mRNAs were involved in pathways in cancer. As a benign disorder, endometriosis behaves similarly to malignant tumors in many respects. A nationwide cohort study investigated the risk of nongynecological cancers in women with surgically verified endometriosis and found that endometriosis was associated with an increased risk of thyroid cancer (standardized incidence ratio [SIR]: 1.43; 95% confidence intervals [CI s]: 1.23–1.64) and basal cell carcinoma (SIR: 1.18; 95% CI: 1.10–1.25).[24] It follows that there is a certain association between endometriosis and cancer, and some studies from the perspective of cancer may obtain new discoveries.

Beside the comparisons between ectopic and normal endometrium, eutopic and normal endometrium, and ectopic and eutopic endometrium, our study analyzed the common differences of lncRNA and mRNA expression in ectopic and eutopic endometrium compared with normal endometrium for the first time that were probably involved in the pathogenesis of endometriosis based on the interactions in the complex coding–non-coding gene coexpression network. While the functions of many lncRNAs are poorly understood and some specific genes and pathways in endometriosis pathogenesis have already been reported, the present study provides an overall perspective of lncRNAs and interaction profiles that can provide further insight into the pathogenesis of endometriosis.

In conclusion, this study was the first to apply RNA-sequencing to analyze the differential expression profiles of mRNAs and lncRNAs in endometriosis, which included the analyses between ectopic and normal endometrium, eutopic and normal endometrium, and ectopic and eutopic endometrium. Functional annotations showed that some lncRNAs were involved in important biological processes associated with endometriosis by affecting their coexpressed mRNAs. This study provided an overall perspective of lncRNAs and its interaction profile in endometriosis. The dysregulated lncRNAs identified in this study can be used as potential diagnostic biomarkers and therapeutic targets. Future studies should focus on elucidating specific molecular mechanisms of the candidate lncRNAs to provide novel insights into endometriosis.

Supplementary information is linked to the online version of the paper on the Reproductive and Developmental Medicine website.

Financial support and sponsorship

This study was supported by the 333 Project Foundation of Jiangsu (No. BRA2017146) and the Key Talents Project of Maternal and Child Health in Jiangsu (No. FRC201730).

Conflicts of interest

There are no conflicts of interest.



 
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