Integrated analysis of the transcriptome-wide m6A methylome in preeclampsia and healthy control placentas

Wang, Jin; Gao, Fengchun; Zhao, Xiaohan; Cai, Yan; Hua, Jing

doi:10.7717/peerj.9880

Cited by 24 publications

(31 citation statements)

References 54 publications

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“…There were 4,014 differentially m6A peaks, corresponding to 2,144 genes, and each gene was associated with at least one or more m6A peaks. The distribution of m6A peaks appeared in the CDS, which was also consistent with other diseases such as cancer (Zhang et al, 2020b), traumatic brain injury (Yu et al, 2020), and preeclampsia (Wang et al, 2020a). After PNI, these m6A peaks preferentially located at the start codons (19.17 vs. 17.49%), and there was a decreasing trend in the CDS (66.75 vs. 68.49%).…”

Section: Discussionsupporting

confidence: 76%

Epitranscriptomic Analysis of m6A Methylome After Peripheral Nerve Injury

Zhang

Hao

et al. 2021

Front. Genet.

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N6-methyladenosine (m6A) is one of the most plentiful internal RNA modifications, especially in eukaryotic messenger RNA (mRNA), which plays pivotal roles in the regulation of mRNA life cycle and nerve development. However, the mRNA m6A methylation pattern in peripheral nervous injury (PNI) has not been investigated. In this study, sciatic nerve samples were collected from 7 days after sciatic nerve injury (SNI) and control rats. Quantitative real-time PCR demonstrated that m6A-related methyltransferase/demethylase genes were remarkably upregulated in SNI group compared with control group. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was performed to reveal the m6A methylation landscape. The results showed that 4,014 m6A peaks were significantly altered, including 2,144 upregulated and 1,870 downregulated m6A peaks, which were corresponded to 1,858 genes. Moreover, 919 differentially expressed genes were identified by the conjoint analysis of MeRIP-seq and RNA-seq. GO and KEGG pathway analyses were performed to determine the biological functions and signaling pathways of the m6A-modified genes. Notably, these genes were mainly related to the immune system process, cell activation, and nervous system development in GO analysis. KEGG pathway analysis revealed that these genes were involved in the cell cycle, B cell receptor signaling pathway, axon guidance pathway, and calcium signaling pathway. Furthermore, the m6A methylation and protein expression levels of autophagy-related gene (Atg7) were increased, together with the activation of autophagy. These findings shed some light on the epigenetic regulation of gene expression, which may provide a new opinion to promote functional recovery after PNI.

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Section: Discussionsupporting

confidence: 76%

Epitranscriptomic Analysis of m6A Methylome After Peripheral Nerve Injury

Zhang

Hao

et al. 2021

Front. Genet.

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“…The number of reports regarding the profiling of m6A modification and its potential role in the placenta of PE is small. Several studies have investigated the clinical features in PE patients and healthy controls and found no difference in maternal age in the whole group [ 17 , 18 ]. Currently, no study has analysed the correlation between maternal age and m6A levels in PE patients, and our results need to be further explored.…”

Section: Discussionmentioning

confidence: 99%

“…Given the indispensable function of RNA m6A modification in various bioprocesses, it is reasonable to speculate that deregulation of m6A modification may also be associated with PE. Recent studies showed that METTL3 and METTL14 were upregulated in PE and verified that the significant increase in HSPA1A mRNA and protein expression was regulated by m6A modification, suggesting that m6A plays a key role in the regulation of gene expression [ 18 ]. Increased METTL3 expression and m6A RNA methylation were also observed by Taniguchi et al, and they suggested that aberrant m6A modification may contribute to trophoblast dysfunction in PE [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Gene model-related m6A expression levels predict the risk of preeclampsia

Chen

Diao

et al. 2022

BMC Med Genomics

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Background This is the first study to explore the potential functions and expression patterns of RNA N6-methyladenosine (m6A) and potential related genes in preeclampsia. Methods We identified two m6A modification patterns through unsupervised cluster analysis and validated them by principal component analysis. We quantified the relative abundance of specific infiltrating immunocytes using single-sample gene set enrichment analysis (ssGSEA) and the Wilcoxon test. To screen hub genes related to m6A regulators, we performed weighted gene coexpression network analysis. Functional enrichment analysis was conducted for differential signalling pathways and cellular processes. Preeclampsia patients were grouped by consensus clustering based on differentially expressed hub genes and the relationship between different gene-mediated classifications and clinical features. Results Two m6A clusters in preeclampsia, cluster A and cluster B, were determined based on the expression of 17 m6A modification regulators; ssGSEA revealed seven significantly different immune cell subtypes between the two clusters. A total of 1393 DEGs and nine potential m6A-modified hub genes were screened. We divided the patients into two groups based on the expression of these nine genes. We found that almost all the patients in m6A cluster A were classified into hub gene cluster 1 and that a lower gestational age may be associated with more m6A-associated events. Conclusions This study revealed that hub gene-mediated classification is consistent with m6A modification clusters for predicting the clinical characteristics of patients with preeclampsia. Our results provide new insights into the molecular mechanisms of preeclampsia.

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“…Li et al mapped the m 6 A modification profile of preeclampsia placenta and found that METTL3 and METTL14 were up-regulated in preeclampsia. Differential m 6 A-modified transcripts are primarily associated with the nitrogen compound metabolic process, positive regulation of vascular-associated smooth muscle cell migration, and several cancer-related pathways ( Wang et al, 2020a ). Li et al also found that the reduced methylation of m 6 A in RSA villous may inhibit the invasion of villous cells and lead to RSA ( Wang et al, 2020a ).…”

Section: Introductionmentioning

confidence: 99%

“…Differential m 6 A-modified transcripts are primarily associated with the nitrogen compound metabolic process, positive regulation of vascular-associated smooth muscle cell migration, and several cancer-related pathways ( Wang et al, 2020a ). Li et al also found that the reduced methylation of m 6 A in RSA villous may inhibit the invasion of villous cells and lead to RSA ( Wang et al, 2020a ). However, whether m 6 A modification can lead to RSA and its exact mechanisms still need to be proved by a large number of studies.…”

Section: Introductionmentioning

confidence: 99%

METTL3-Mediated m6A RNA Methylation of ZBTB4 Interferes With Trophoblast Invasion and Maybe Involved in RSA

Huang

Zhang

et al. 2022

Front. Cell Dev. Biol.

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N6-methyladenosine (m6A) was the most abundant modification of mRNA and lncRNA in mammalian cells and played an important role in many biological processes. However, whether m6A modification was associated with recurrent spontaneous abortion (RSA) and its roles were still unclear.Methods: Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) was used to study the global m6A modification pattern in RSAs and controls. RNA sequencing (RNA-Seq) was used to study the level of global mRNA in two groups. Real-time quantitative PCR (RT-qPCR) was used to verify the level of mRNA of METTL3 and ZBTB4. MeRIP–qPCR was conducted to test the level of ZBTB4 m6A modification in two groups. In order to further explore whether ZBTB4 was the substrate of METTL3, the HTR-8/SVneo (HTR-8) cell line was selected for the knockdown and overexpression of METTL3. To study whether METTL3 regulated the ZBTB4 expression by recognizing ZBTB4 mRNA m6A motifs in coding sequences (CDS), dual-luciferase reporter assay was conducted. RNA stability assays using actinomycin D were conducted to study the RNA stability of the HTR-8 cell line with METTL3 overexpression and knockdown. To illustrate the role of METTL3 in the invasion of trophoblast, matrigel invasion assays and transwell migration assays were conducted using the HTR-8 cell line with METTL3 overexpression and knockdown.Results: A total of 65 genes were found with significant differences both in m6A modification and mRNA expression. We found m6A methyltransferase METTL3 was significantly down-regulated in the RSA group. Through gene function analysis, RT-qPCR, MeRIP–qPCR validation experiment, knockdown, and overexpression of METTL3 in the HTR-8 cell line, ZBTB4 was selected as one target of METTL3. Furthermore, we clarified that METTL3 regulated the expression of ZBTB4 by recognizing ZBTB4 mRNA m6A motifs in the CDS using the dual-luciferase reporter assay and METTL3 regulated the invasion of trophoblast by altering the stability and expression of ZBTB4 by RNA stability, matrigel invasion, and transwell migration assays.Conclusion: Our study revealed the mechanism by which METTL3 regulated the stability and expression of ZBTB4 and the trophoblast migration ability of RSA. A new perspective was provided for exploring the mechanism of embryonic development in RSA patients.

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Integrated analysis of the transcriptome-wide m6A methylome in preeclampsia and healthy control placentas

Cited by 24 publications

References 54 publications

Epitranscriptomic Analysis of m6A Methylome After Peripheral Nerve Injury

Epitranscriptomic Analysis of m6A Methylome After Peripheral Nerve Injury

Gene model-related m6A expression levels predict the risk of preeclampsia

METTL3-Mediated m6A RNA Methylation of ZBTB4 Interferes With Trophoblast Invasion and Maybe Involved in RSA

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