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Methylation alterations of imprinted genes in different placental diseases

Clinical Epigenetics volume 16, Article number: 132 (2024) Cite this article

Abstract

Background

Imprinted genes play important functions in placentation and pregnancy; however, research on their roles in different placental diseases is limited. It is believed that epigenetic alterations, such as DNA methylation, of placental imprinting genes may contribute to the different pathological features of severe placental diseases, such as pre-eclampsia (PE) and placenta accreta spectrum disorders (PAS).

Results

In this study, we conducted a comparative analysis of the methylation and expression of placental imprinted genes between PE and PAS using bisulfite sequencing polymerase chain reaction (PCR) and quantitative PCR, respectively. Additionally, we assessed oxidative damage of placental DNA by determining 8-hydroxy-2′-deoxyguanosine levels and fetal growth by determining insulin-like growth factor 2 (IGF2) and cortisol levels in the umbilical cord blood using enzyme-linked immunosorbent assay. Our results indicated that methylation and expression of potassium voltage-gated channel subfamily Q member 1, GNAS complex locus, mesoderm specific transcript, and IGF2 were significantly altered in both PE and PAS placentas. Additionally, our results revealed that the maternal imprinted genes were significantly over-expressed in PE and significantly under-expressed in PAS compared with a normal pregnancy. Moreover, DNA oxidative damage was elevated and positively correlated with IGF2 DNA methylation in both PE and PAS placentas, and cortisol and IGF2 levels were significantly decreased in PE and PAS.

Conclusions

This study suggested that DNA methylation and expression of imprinted genes are aberrant in both PE and PAS placentas and that PE and PAS have different methylation profiles, which may be linked to their unique pathogenesis.

Introduction

Genomic imprinting is a conserved gene regulatory mechanism that expresses certain parental genes at specific loci as single alleles by repressing the other parental allele through epigenetic modifications [1], such as DNA methylation [2]. In mammals, imprinted genes are commonly found in clusters on chromosomes, with each cluster containing parent-specific DNA methylation at an imprinting control region to regulate gene expression [1]. During gametogenesis, parental imprinting is established via DNA methylation, which is a stable and inheritable epigenetic marker that regulates the expression of imprinted genes [3].

Numerous studies have demonstrated that imprinted genes participate in key processes of pregnancy, such as uterus decidualization [4], placental angiogenesis [5], and fetal growth and development [6]. For instance, placental tissues of hypertensive pregnant patients have hypomethylation-imprinted maternally expressed H19 transcripts and differentially methylated regions (DMRs) of the insulin-like growth factor 2 (IGF2) gene [7]. In addition, loss of the DMR of potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene is closely associated with the abnormal growth of trophoblast giant cells, while loss of the DMR of paternally expressed 10 (PEG10) is linked to reduced embryonic viability [8]. Moreover, the expression of pleiomorphic adenoma gene-like 1 (PLAGL1) [9], a paternally imprinted gene, is significantly upregulated, while that of mesoderm specific transcript (MEST) and necdin-encoding gene (NDN) is downregulated in pre-eclampsia (PE) patients [10]. Therefore, imprinted genes play crucial roles in placentation, and their abnormal expression can lead to dysregulated placental development and pregnancy disorders [11]. However, information on the roles of imprinted genes in different placental diseases is limited.

Pre-eclampsia (PE) and placenta accreta spectrum disorders (PAS) are the major complications resulting in maternal death and serious adverse pregnancy outcomes in clinic. PAS is characterized by abnormal invasion of trophoblast into the myometrium with elevated placental angiogenesis, while PE is characterized by insufficient placentation and angiogenic imbalance [12]. The epigenetic alterations, such as DNA methylation, of placental imprinting genes may contribute to the different pathological features of PE and PAS. Thus far, there are no studies on the comparative analysis of methylation of placental imprinted genes between PE and PAS and its association with their etiologies. Therefore, in this study, we analyzed the variations in the methylation and expression of placental imprinted genes in PE and PAS. Additionally, we analyzed the oxidative damage of placental DNA and fetal growth in PE and PAS. The results of our study provide novel insights into the pathogenesis of PE and PAS at the epigenetic level.

Methods

Study design and sample collection

This study was approved by the Ethics Committee of the Third Affiliated Hospital of Guangzhou Medical University (Approval No. 2014[085]). The research was conducted according to the Declaration of Helsinki, and informed consent was obtained from all the participants. The study participants were pregnant women of the Chinese Han population who delivered at the Provincial Center for Critical Pregnant Women at the Third Affiliated Hospital of Guangzhou Medical University from August 2015 to December 2020.

The PE and PAS patients were diagnosed according to the clinical guidelines, while healthy pregnant women with a single fetus and without PE, placenta previa, gestational diabetes, or other severe pregnancy complications were considered to be normal term controls (CON). Umbilical cord blood was collected immediately after the delivery and centrifuged at 2000 × g for 15 min to separate serum and blood cells. Placenta samples (~ 1 cm3) were obtained from the fetal side of the placenta and frozen within 30 min after delivery. All the samples were stored in the Biobank of the Third Affiliated Hospital of Guangzhou Medical University until further analysis.

DNA extraction and bisulfite sequencing (BS)-polymerase chain reaction (PCR)

Genomic DNA (gDNA) was isolated from the placental tissues using the Magen™ MagPure Tissue DNA KF Kit (Magen, Guangzhou, China) and magnetic bead-based nucleic acid isolation. The base transition of gDNA was performed using the EZ DNA Methylation-Gold™ Kit (ZYMO, USA) according to the manufacturer's instructions. Thereafter, specific loci of the converted target genes were amplified using nested PCR. Table S1 lists the PCR primers used for nested PCR. The methylation levels of the target genes were analyzed by sequencing the PCR-amplified products after bisulfite conversion, as described in previous literature [13]. To analyze the stability of the method, three DNA samples were mixed and divided into three tubes and subjected to bisulfite treatment and PCR amplification. Thereafter, half of the amplified products from each tube were mixed and divided into three tubes. Lastly, the samples of the six tubes were sequenced, and the coefficients of variation (CV) of the methylation levels at the analyzed CpG sites were determined. Genes with CVs ≤ 15% were selected for further analysis.

RNA extraction and quantitative PCR (qPCR)

Total RNA was isolated from the placental tissues using Trizol (Invitrogen, Shanghai, China). Approximately 1 μg of RNA was used for complementary DNA synthesis using the PrimeScript™ RT reagent Kit with gDNA Eraser (Takara, Japan). Thereafter, real-time quantification was conducted using the GoTaq qPCR Master Mix (Promega, USA) on the QuantStudio™ 6 Flex System real-time PCR machine (Applied Biosystems, Germany).The relative gene expression was calculated with the 2−ΔΔCT method using the glyceraldehyde 3-phosphate dehydrogenase gene as the internal reference.

Enzyme-linked immunosorbent assay (ELISA)

The 8-hydroxy-2'-deoxyguanosine (8-OHdG) ELISA Kit (ab201734, Abcam, Shanghai, China) was used for the detection of oxidative DNA damage. The IGF2 (EK14678, SAB, Shanghai, China) and DLK1 (DY1144-05, R&B, Chengdu, China) assay kits were used for the detection of IGF2 and DLK1 levels, respectively, in the cord blood serum (CBS) samples. Lastly, the cotinine (Calbiotech, USA) and cortisol (Abnova, Taiwan) test kits were used to measure the cotinine and cortisol levels, respectively, in the CBS samples. All the ELISA experiments were performed according to the manufacturer’s instructions.

Statistical analysis

All data were statistically analyzed using the SPSS software v20.0 (SPSS, Inc., Chicago, IL, USA) and GraphPad Prism software v9.0 (GraphPad Software, San Diego, CA, USA).The independent sample t-test was used to compare data between two groups, and a one-way analysis of variance was used to compare data between multiple groups. Categorical data were represented as frequency and percentage, and continuous data were represented as the mean ± SD or SEM. The P-value < 0.05 was considered statistically significant.

Results

Selection of imprinted genes

We selected 23 imprinted genes from the Geneimprint, Genecards, and Genebank databases for BS-PCR amplification with < 15% CV. Table S1 lists the information on these 23 target genes. Among the 23 imprinted genes, 8 were maternally expressed, 14 were paternally expressed, and 1 was biparentally expressed.

Study participants

A total of 583 participants were enrolled in this study for the methylation analysis of placental imprinted genes. These participants were divided into screening and validation cohorts. The screening cohort consisted of 20 PAS cases, 20 PE cases, and 20 CON participants, while the validation cohort consisted of 136 PAS cases, 288 PE cases, and 99 CON participants. In addition, part of the samples were further used for the detection of placental oxidative DNA damage (28 PAS cases, 28 PE cases, and 24 CON participants), placental gene expression analysis (17 PAS cases, 31 PE cases, and 21 CON participants), and serological analysis of umbilical cord blood (30 PAS cases, 30 PE cases, and 24 CON participants). Fig. S1 demonstrates the experimental design.

A comparison of the clinical data showed that systolic blood pressure, diastolic blood pressure, and urine protein were significantly higher in the PE groups than in the PAS and CON groups in both the screening and validation cohorts (Tables 1 and 2; P < 0.05). Additionally, pregnancy outcome-related parameters, such as gestational week at birth, preterm birth rate, and birth weight, were significantly lower in both the PE and PAS groups than in the CON groups in both cohorts (Tables 1 and 2; P < 0.05).

Table 1 Clinical information of the patients in the screening cohort
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Table 2 Clinical information of the patients in the validation cohort
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Alternation in the methylation of the target imprinted genes in the screening cohort

Analysis of the methylation levels of the 23 imprinted genes revealed that only 8 genes showed methylation alterations in the PE and PAS groups. Figure 1 shows the average methylation levels of these eight imprinted genes. The data demonstrated that the average methylation level of MEST decreased in the PE group, while that of KCNQ1 increased in the PE and PAS groups compared with the CON group (P < 0.05 and P < 0.01; Fig. 1D and F).

Fig. 1
figure 1

Average methylation levels of the imprinted genes in the screening cohort. A PEG3, B GNAS, C IGF2, D MEST, E DLK1, F KCNQ1, G RB1, and H PEG10. Vertical coordinates represent the average DNA methylation level in the analyzed DMR. CON, normal term controls; PAS, placenta accreta spectrum; and PE, pre-eclampsia. Data are represented as the mean ± SEM; *P < 0.05 and **P < 0.01

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Figure 2 demonstrates the methylation levels at each CpG site in the DMR of the imprinted genes in the screening cohort. The results showed that IGF2, GNAS complex locus (GNAS), MEST, DLK1, KCNQ1, and paternally expressed 3 (PEG3) had significantly different DNA methylation modifications at a single CpG site in the PE, PAS, and CON groups (P < 0.05; Fig. 2). Moreover, the methylation level at specific CpG sites of IGF2, MEST, and DLK1 decreased, while that of GNAS, KCNQ1, and PEG3 increased in the PAS and/or PE groups compared with the CON group (P < 0.05; Fig. 2).

Fig.2
figure 2

Methylation levels at individual CpG sites in the DMR of the imprinted genes in the screening cohort. A IGF2, B GNAS, C MEST, D DLK1, E KCNQ1, F RB1, G PEG10, and H PEG3. Vertical coordinates represent the methylation level, and the horizontal axis represents specific CpG sites in the analyzed DMR. CON, normal term controls; PAS, placenta accreta spectrum; and PE, pre-eclampsia. Data are represented as the mean ± SEM; *P < 0.05, **P < 0.01, and ***P < 0.001

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Alternation in the methylation of the target imprinted genes in the validation cohort

Based on the previous results, methylation levels of KCNQ1, MEST, GNAS, and IGF2 were further analyzed in the validation cohort. Figure 3 presents the average DNA methylation levels of KCNQ1, MEST, GNAS, and IGF2 in the validation cohort. The data showed that the average methylation levels of KCNQ1 increased significantly, while that of IGF2 decreased significantly in the PE and PAS groups compared with the CON group (P < 0.001; Fig. 3A and D). In addition, the average methylation level of GNAS decreased significantly in PAS but was unaltered in the PE group compared with the CON group (P < 0.001; Fig. 3C).

Fig.3
figure 3

Average methylation levels of the imprinted genes in the validation cohort. A KCNQ1, B MEST, C GNAS, and D IGF2. Vertical coordinates represent the average DNA methylation level in the analyzed DMR. CON, normal term controls; PAS, placenta accreta spectrum; and PE, pre-eclampsia. Data are represented as the mean ± SEM; **P < 0.01 and ***P < 0.001

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The analysis of the methylation levels at individual CpG sites in the DMR of KCNQ1, MEST, GNAS, and IGF2 showed that the majority of the CpG sites had significantly higher or lower methylation levels in the PAS group than in the CON group (Fig. 4). Meanwhile, in the PE group, the alterations were only found in KCNQ1, MEST, and IGF2 (Fig. 4).

Fig.4
figure 4

Methylation levels at individual CpG sites in the DMR of the imprinted genes in the validation cohort. A KCNQ1, B MEST, C GNAS, and D IGF2.Vertical coordinates represent the methylation level, and the horizontal axis represents specific CpG sites in the analyzed DMR. M and P indicate maternal and paternal allele expression, respectively. CON, normal term controls; PAS, placenta accreta spectrum; and PE, pre-eclampsia. Data are represented as the mean ± SEM; *P < 0.05 and #P < 0.01

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Gene expression analysis of relevant imprinted genes in placental tissues

The expression levels of target imprinted genes in placental tissues were quantified using qPCR (Fig. 5). The results revealed that mRNA expression of DLK1, MEG3, IGF2, H19, and MEST was upregulated in the PE group (P < 0.05) and downregulated in the PAS group (P < 0.001; Fig. 5A–C, E, F, and H). Additionally, the mRNA expression of RB1 was also significantly different between the PE and PAS groups (P < 0.05; Fig. 5B).

Fig.5
figure 5

mRNA expression levels of imprinted genes in the placental tissue of the PE, PAS, and CON groups. A DLK1, B RB1, C MEG3, D PEG3, E IGF2, F H19, G KCNQ1, H MEST, I PLAGL1, J IGF2/H19, and K DLK1/MEG3. CON, normal term controls; PAS, placenta accreta spectrum; and PE, pre-eclampsia. Data are represented as the mean ± SEM;*P < 0.05 and ***P < 0.001

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Additionally, we analyzed the expression of two pairs of contradicting maternal and paternal imprinting genes H19/IGF2 and MEG3/DLK1 in the PE, PAS, and CON groups (Fig. 5J, K). The expression ratios of H19/IGF2 were 4.73, 0.80, and 21.19 and that of MEG3/DLK1 were 2.26, 1.60, and 3.64 in the CON, PAS, and PE groups, respectively. The results indicated that the maternal imprinted genes were significantly over-expressed in PE patients, while the paternal imprinted genes were significantly over-expressed in PAS patients.

Analysis of oxidative DNA damage in placental tissue

The placental tissue samples were analyzed for oxidative DNA damage (Fig. 6). The results showed that the 8-OHdG levels were increased in both PE and PAS groups but were significantly high in the PE group (P < 0.01; Fig. 6A). Additionally, an association analysis indicated that DNA methylation of IGF2 was positively correlated with 8-OHdG levels in the PE (P = 0.1029) and PAS (P = 0.0023) groups, respectively (Fig. 6B and C).

Fig.6
figure 6

Levels of placental imprinted gene methylation, oxidative damage, and fetal growth factors in the PE, PAS, and CON groups. A The 8-OHdG levels in the placental tissue of the PE, PAS, and CON groups. B, C Association between IGF2 DNA methylation and 8-OHdG levels in the PAS and PE groups. D–G The IGF2, DLK1, cortisol, and cotinine levels in the umbilical CBS of the PE, PAS, and CON groups. CON, normal term controls; PAS, placenta accreta spectrum; and PE, pre-eclampsia. Data are represented as the mean ± SEM;*P < 0.05, **P < 0.01, and ***P < 0.001

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Detection of IGF2, DLK1, cortisol, and cotinine levels in umbilical CBS

The IGF2, DLK1, cortisol, and cotinine levels in the umbilical CBS samples of the PE, PAS, and CON groups were detected using ELISA (Fig. 6D–F). The results revealed that IGF2 and cortisol levels were significantly decreased in the PE and PAS groups compared with the CON group (P < 0.001; Fig. 6D and E), while DLK1 and cotinine levels were not significantly different between the three groups (Fig. 6F and G).

Discussion

In this study, we found significant variations in DNA methylation of imprinted genes in the PE and PAS samples compared with the normal control samples. Moreover, there were specific methylation alteration profiles and different maternal/paternal allele expression ratios of placental imprinted genes in the PE and PAS samples, and a strong correlation between elevated oxidative stress and methylation alterations of imprinted genes. These results indicate that methylation alterations of imprinted genes may be specific to different placental diseases and may be associated with placentation and fetal development.

Our data demonstrated significant differences in the DNA methylation of imprinted genes in the PE and PAS samples. For example, in PE, KCNQ1 was significantly hypermethylated, and IGF2 was hypomethylated, while in PAS, KCNQ1 was significantly hypermethylated, and IGF2 and GNAS were hypomethylated. KCNQ1 belongs to a family of voltage-dependent potassium channels, which is associated with blood pressure in patients with PE [14], and alterations in its expression can affect vascularization, nutrient transport, and placental development [15]. Our results showed that the KCNQ1 enhancer region was hypermethylated in both PE and PAS patients, suggesting that the regulation of KCNQ1 gene expression may play an important role in the pathogenesis of PE and PAS. GNAS participates in the G-protein-coupled receptor signal transduction pathway, intracellular signaling, and cell differentiation [16] and acts as an epigenetic biomarker in several malignancies [17]. In this study, we found that GNAS was significantly hypomethylated in PAS, suggesting that the excessive cell invasion [18], immune escape [19], and induced angiogenesis [20] in PAS may be similar to those in tumors. IGF2 participates in nutrient transport in the placenta and plays an important function in placental growth and development [21], and alternations in its expression may adversely affect the course of pregnancy. Our results showed that IGF2 was hypomethylated in both PE and PAS groups, consistent with the previous reports [7], indicating abnormal placental development in both PE and PAS patients.

Genomic imprinting, regulated through epigenetic modifications, is a mechanism for allocating resources, as the products of paternally expressed genes tend to promote fetal growth, while that of maternally expressed genes tend to inhibit fetal growth [22]. It is believed that this conflict between the expression of maternal and paternal alleles is an important pathogenic factor in PE [22, 23], and our current study demonstrated that this conflict may also contribute to the etiology of PAS. In this study, the maternal imprinted genes H19 and MEG3 were over-expressed compared with the paternal imprinted genes IGF2 and DLK1 in PE. In contrast, H19 and MEG3 were under-expressed compared with IGF2 and DLK1 in PAS. Moreover, the expression ratios of the maternal/paternal imprinted gene pairs were significantly increased in PE but decreased in PAS, compared with the CON. These results are consistent with the pathologic characteristics of PE and PAS, as PE is characterized by retarded placentation, while PAS is characterized by invaded placentation, suggesting that different epigenetic mechanisms are involved in their etiologies.

Recent studies have demonstrated the effect of environmental factors on DNA methylation in the placenta and found that variations in DNA methylation in the placenta [24], due to oxidative stress or environmental factors, are correlated with multiple pregnancy disorders [25]. For instance, high levels of 8-OHdG, a marker of oxidative DNA damage, have been reported in the umbilical cord blood of PE patients [26]. Our study also confirmed that 8-OHdG levels were significantly elevated in both PE and PAS placentas, consistent with the results of the LIFECODES cohort study [27], indicating high oxidative stress in abnormal placentas. Additionally, in this study, we found a positive correlation between DNA methylation of the IGF2 gene and 8-OHdG levels in the PE and PAS placentas, suggesting that placental oxidative stress affects DNA methylation of imprinted genes. DNA damage and genomic instability caused by oxidative stress are major drivers of tumorigenesis [28]. During pregnancy, oxidative stress can alter the oxygen tension in the placental interstitial space, damage intracellular macromolecules, interfere with the normal differentiation and invasive capacity of the trophoblasts, and alter the maternal inflammatory response [29,30,31,32]. Therefore, an abnormal increase in oxidative stress and DNA damage may cause a dysregulation in the methylation and expression of placental imprinted genes and contribute to the occurrence of placental diseases.

In this study, we found that IGF2 levels were significantly decreased in the CBS of PE and PAS patients, consistent with previous reports [33]. IGF2 is essential for nutrient transportation in the placenta, and its decreased expression in cord blood may indicate impaired placentation and vascular function in PE and PAS [34]. Cortisol plays important functions in both fetal development and placental lipid metabolism pathway [35, 36], and its decreased levels in the CBS indicated impaired fetal growth and development in the PE and PAS groups. Altogether, our results suggested a strong correlation between placental DNA damage, altered IGF2 imprinting and expression, and interrupted fetal development in placental diseases.

Conclusions

The current study found that methylation and expression of the placental imprinted genes KCNQ1, GNAS, MEST, and IGF2 were significantly altered in PE and PAS placentas. The maternal imprinted genes were significantly over-expressed in PE but significantly under-expressed in PAS compared with the CON. Moreover, the level of oxidative DNA damage was elevated and positively correlated with IGF2 DNA methylation in both PE and PAS placentas. In addition, the cortisol levels and fetal IGF2 expression were significantly decreased in both PE and PAS. Therefore, our results indicated that DNA methylation and expression of imprinted genes were aberrant in the placental diseases PE and PAS and that different placental diseases have varied epigenetic etiologies, which are significantly associated with their pathological features.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

Funding

This work was supported by the National Key R&D Program of China (No. 2022YFC2704500) and the Project of Guangzhou Science, Technology, and Innovation Commission (Grant No. 2023A03J0379).

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Author notes

  1. Xuwei Wang and Yunyun Liu have contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, No.63 Duobao Road, Liwan District, Guangzhou, 510150, Guangdong, China

    Xuwei Wang, Si Yang, Yuhan Yang, Dunjin Chen & Bolan Yu

  2. Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Xuwei Wang, Yunyun Liu, Si Yang, Yuhan Yang, Dunjin Chen & Bolan Yu

  3. The Third Clinical College of Guangzhou Medical University, Guangzhou, China

    Yuying Wu & Chunxi Lin

  4. BioResource Research Center, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Si Yang & Bolan Yu

Authors
  1. Xuwei Wang
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  2. Yunyun Liu
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  3. Yuying Wu
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  4. Chunxi Lin
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  5. Si Yang
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  6. Yuhan Yang
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  7. Dunjin Chen
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  8. Bolan Yu
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Contributions

B.Y. designed and supervised research studies. X.W. and Y.L. conducted the experiments and wrote the manuscript draft. Y.W. and C.L. helped to write the manuscript. S.Y. and Y.Y. interpreted the clinical data. D.C. helped the collection of clinical samples. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Bolan Yu.

Ethics declarations

Ethics approval and consent to participate

This study was conducted with the approval (No. 2014[085], approval date August 2014) of the Ethics Committee of the Third Affiliated Hospital of Guangzhou Medical University. The research was carried out according to the Declaration of Helsinki, and informed consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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Cite this article

Wang, X., Liu, Y., Wu, Y. et al. Methylation alterations of imprinted genes in different placental diseases. Clin Epigenet 16, 132 (2024). https://doi.org/10.1186/s13148-024-01738-3

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  • DOI: https://doi.org/10.1186/s13148-024-01738-3

Keywords

Clinical Epigenetics

ISSN: 1868-7083

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