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Embryonic stem cells (mESCs), having potential to differentiate into three germ-layer cells including cardiomyocytes, shall be a perfect model to help understanding heart development. Here, using small RNA deep sequencing, we studied the small RNAome in the early stage of mouse cardiac differentiation. We found that the expression pattern of most m...
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... identify the possible biological functions of differentially ex- pressed miRNA during cardiac differentiation, we examined the path- ways and functions that are associated with their predicated target mRNAs. Therefore, their targets were predicted and extracted for pathway enrichment analysis. GeneGo was employed as the functional annotation system (Fig. 2). Ten highly representative pathways ranked by their respective p-values are shown in Table ...
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We have established an in vitro model of the human congenital heart defect (CHD)–associated mutation NKX2.5 R141C. We describe the use of the hanging drop method to differentiate Nkx2.5R141C/+ murine embryonic stem cells (mESCs) along with Nkx2.5+/+ control cells. This method allows us to recapitulate the early stages of embryonic heart development...
Citations
... This process represents the essential characteristics of cardiac differentiation in vivo, thereby providing a suitable model for cell or organ development, in health and disease [108,109]. Li et al. utilized multiple samples collected at sequential time points during mouse embryonic pluripotent stem cells (day 0) change to contracting cardiomyocytes (day 9) and retrieved piRNA expression using next-generation RNA sequencing [110]. The presence of piRNAs during this process was confirmed, and the normalized expression profile showed dynamic expression patterns of individual piRNAs [110]. ...
... Li et al. utilized multiple samples collected at sequential time points during mouse embryonic pluripotent stem cells (day 0) change to contracting cardiomyocytes (day 9) and retrieved piRNA expression using next-generation RNA sequencing [110]. The presence of piRNAs during this process was confirmed, and the normalized expression profile showed dynamic expression patterns of individual piRNAs [110]. With few exceptions, almost all piRNAs were mapped to unique locations in intergenic areas [110]. ...
... The presence of piRNAs during this process was confirmed, and the normalized expression profile showed dynamic expression patterns of individual piRNAs [110]. With few exceptions, almost all piRNAs were mapped to unique locations in intergenic areas [110]. More recently, Greca et al. extended the observation window to 21 days to characterize piRNA expression from embryonic pluripotent stem cells (day 0) to cardiomyocytes (day 21) in humans [93]. ...
Piwi-interacting RNAs (piRNAs) are a novel group of small non-coding RNA molecules with lengths of 21–35 nucleotides, first identified from the germline. PiRNAs and their associated PIWI clade Argonaute proteins constitute a key part of the piRNA pathway, with the best-known biological function to silence transposable elements in germ cells. The piRNA pathway, in fact, is not exclusive to the germline. Somatic functions of piRNAs have been recorded since their first discovery. To date, involvement of the piRNA pathway has been identified within the biological functions of genome rearrangement, epigenetic regulation, protein regulation in the germline and/or the soma transcriptionally or post-transcriptionally. Emerging evidence has shown that the piRNA pathway is essential for the normal function of the cardiovascular system and that its abnormal expression is correlated with cardiovascular dysfunction, although comprehensive roles of the piRNA pathway in the cardiovascular system and underlying mechanisms remain unclear. In this review, we discuss current findings of piRNA pathway expression in cardiac cell types and their potential functions in cardiac differentiation, repair and regeneration, thus providing new insights into cardiovascular disease development associated with the piRNA pathway.
... Their expression levels change during different developmental stages. 32 Additionally, piRNAs exist in cardiac progenitor cells, 33 suggesting that piRNA may play an important role in the process of heart regeneration and participate in the maintenance F I G U R E 3 piRNA participates in methylation regulation. The complex that includes piRNA, PIWI, Arx and Panx induces cotranscriptional inhibition. ...
PIWI‐interacting RNAs (piRNAs) are recently discovered small non‐coding RNAs consisting of 24‐35 nucleotides, usually including a characteristic 5‐terminal uridine and an adenosine at position 10. PIWI proteins can specifically bind to the unique structure of the 3′ end of piRNAs. In the past, it was thought that piRNAs existed only in the reproductive system, but recently, it was reported that piRNAs are also expressed in several other human tissues with tissue specificity. Growing evidence shows that piRNAs and PIWI proteins are abnormally expressed in various diseases, including cancers, neurodegenerative diseases and ageing, and may be potential biomarkers and therapeutic targets. This review aims to discuss the current research status regarding piRNA biogenetic processes, functions, mechanisms and emerging roles in various diseases.
... piRNAs in MIRI piRNAs are 26-30 nucleotides in length and bind to PIWI proteins [212], which were initially discovered in germline cells as key mediators for germline maintenance [213]. piRNAs are actually expressed in a variety of somatic cells, including pluripotent, brain, liver, kidney, heart and cancer cells [214][215][216]; they modulate gene expression in somatic cells through transposon silencing, epigenetic programming, DNA rearrangements, mRNA turnover and translational control [212]. It is known that the occurrence and development of diseases such as cancer could be influenced by the dysregulation of piRNAs. ...
... Recently, 447 piRNA transcripts were identified from mesoderm progenitors and cardiomyocytes, of which 218 were detected in mesoderm and 171 in cardiac cells, indicating that genes hosting piRNA transcripts in cardiac tissues play a role in critical biological processes involving the heart [214]. Additionally, a study investigating the small RNAome in the early stages of mouse cardiac differentiation by small RNA deep sequencing demonstrated the existence of piRNAs and their differential expression in this process [215]. Yang et al. analyzed serum exosomes from patients with heart failure and found that 585 piRNAs were upregulated and 4623 were downregulated; among these latter piRNAs, has-piR-020009 and has-piR-006426 were the most downregulated [220]. ...
The morbidity and mortality of myocardial ischemia reperfusion injury (MIRI) have increased in modern society. Noncoding RNAs (ncRNAs), including lncRNAs, circRNAs, piRNAs and miRNAs, have been reported in a variety of studies to be involved in pathological initiation and developments of MIRI. Hence this review focuses on the current research regarding these ncRNAs in MIRI. We comprehensively introduce the important features of lncRNAs, circRNAs, piRNA and miRNAs and then summarize the published studies of ncRNAs in MIRI. A clarification of lncRNA–miRNA–mRNA, lncRNA–transcription factor–mRNA and circRNA–miRNA–mRNA axes in MIRI follows, to further elucidate the crucial roles of ncRNAs in MIRI. Bioinformatics analysis has revealed the biological correlation of mRNAs with MIRI. We provide a comprehensive perspective for the roles of these ncRNAs and their related networks in MIRI, providing a theoretical basis for preclinical and clinical studies on ncRNA-based gene therapy for MIRI treatment.
... PIWI-interacting RNAs (piRNAs) are another class of short noncoding regulatory RNAs with an estimated size of 26À31 nucleotides [19]. These RNAs bind to PIWI proteins, which function in the differentiation of embryonic stem cells and in early embryonic development [20,21], piRNAs regulate gene expression through an miRNAlike base complementary mechanism that is essential for embryonic development [22]. Satellite repeats regulate global gene expression in trans via piRNA-mediated gene silencing, which is essential for embryonic development; indeed, the deletion of tapiR1 leads to embryonic stagnation in Aedes [23]. ...
Background
Congenital malformations are common birth defects with high neonatal morbidity and mortality. It is essential to find simpler and more efficient biomarkers for early prenatal diagnosis. Therefore, we investigated PIWI-interacting RNAs (piRNAs) as potential prenatal biomarkers in plasma-derived exosomes from pregnant women carrying foetuses with congenital malformations.
Methods
Small RNA sequencing was used to screen piRNA biomarkers in plasma-derived exosomes of five pregnant women carrying foetuses with nonsyndromic cleft lip and palate (nsCLP) and five women carrying normal foetuses. Differentially expressed piRNAs were verified in 270 pregnant women, including 111 paired women carrying foetuses with congenital malformations and normal foetuses (at 24 gestational weeks), 10 paired women carrying foetuses with nsCLP and normal foetuses (at 15–19 gestational weeks), and 28 women at different stages of normal pregnancy. piRNA biomarkers were also verified in placentas, umbilical cords, fetal medial calf muscles, and lip tissues of nsCLP and normal foetuses.
Findings
We identified a biomarker panel of three pregnancy-associated exosomal piRNAs (hsa-piR-009228, hsa-piR-016659, and hsa-piR-020496) could distinguish nsCLP foetuses from normal foetuses. These three piRNAs had better diagnostic accuracy for nsCLP at the early gestational stage, at which time typical malformations were not detected upon prenatal ultrasound screening, and had diagnostic value for neural tube defects (NTDs) and congenital heart defects (CHDs).
Interpretation
Our work revealed the potential clinical applications of piRNAs for predicting nsCLP, NTDs, and CHDs.
Funding
National Key Research and Development Program, National Natural Science Foundation of China, and LiaoNing Revitalization Talents Program .
... Due to the availability of high-throughput transcriptome sequencing, piRNAs were discovered to be differentially expressed in patients with CVDs, and subsequently, their potential regulatory functions and underlying mechanisms were investigated. To date, accumulating evidence reveals that piRNAs may be essential contributors to the development of CVDs, such as myocardial ischemia, chronic thromboembolic pulmonary hypertension (CTEPH), cardiac hypertrophy, cardiac regeneration, cardiac differentiation, myocardial infarction (MI), and heart failure (HF) [12][13][14][15][16][17] . Notably, studies focusing on the involvement of piRNAs in CVDs gradually attracted more attention, resulting in a significant improvement in understanding of the relationship between piRNAs and CVDs. ...
... In 2014, Rajana et al. investigated the function of piRNAs and concluded that piRNAs are associated with the AKT signaling pathway [12]. Furthermore, piRNAs acting on the Stat3/bcl-xl signaling pathway, in which ATK is one of the important downstream target genes, has been shown to inhibit tumor cell apoptosis [16]. Interestingly, the expression of methyl CpG binding protein 2 (MeCP2) in the cardiomyocytes activates the erk1/2-Egr-1 signal, inhibits the AKT/p38 signal, and promotes cell proliferation, while MeCP2 inactivation leads to a surge in the total piRNA population. ...
... Nevertheless, the mechanisms that drive cardiac transformation are largely unknown. As early as a decade ago, piRNAs were found to be expressed during cardiac differentiation, with 20 piRNAs identified to have the highest expression levels, while several key transcriptomes were found to change during this process [16]. For example, piR-1078, which was slightly expressed on day 0 of differentiation, increased by nine times on day 2 and then gradually decreased, suggesting that piRNAs may be important regulators of myocardial differentiation [16]. ...
Cardiovascular diseases (CVDs) are the leading causes of death worldwide. Increasing reports demonstrated that non-coding RNAs (ncRNAs) have been crucially involved in the development of CVDs. Piwi-interacting RNAs (piRNAs) are a novel cluster of small non-coding RNAs with strong uracil bias at the 5′ end and 2′-O-methylation at the 3′ end that are mainly present in the mammalian reproductive system and stem cells and serve as potential modulators of developmental and pathophysiological processes. Recently, piRNAs have been reported to be widely expressed in human tissues and can potentially regulate various diseases. Specifically, concomitant with the development of next-generation sequencing techniques, piRNAs have been found to be differentially expressed in CVDs, indicating their potential involvement in the occurrence and progression of heart diseases. However, the molecular mechanisms and signaling pathways involved with piRNA function have not been fully elucidated. In this review, we present the current understanding of the piRNAs from the perspectives of biogenesis, characteristics, biological function, and regulatory mechanisms, and highlight their potential roles and underlying mechanisms in CVDs, which will provide new insights into the potential applications of piRNAs in the clinical diagnosis, prognosis, and therapeutic strategies for heart diseases.
... Among the different types of ncRNA, the influence of piRNAs, a distinct class of small ncRNAs that are 26-32-nucleotides long, in cardiac physiology and the pathogenesis of various diseases remains largely unknown, even though they are abundantly expressed in cardiac tissue 18,19 . A dynamic and specific expression pattern of piRNAs is observed during cardiomyocyte differentiation from pluripotent cells 20 . piRNA expression is also highly altered during various stress conditions, such as myocardial infarction and hypertrophy, but their functions remain elusive 18,19 . ...
PIWI-interacting RNAs (piRNAs) are abundantly expressed during cardiac hypertrophy. However, their functions and molecular mechanisms remain unknown. Here, we identified a cardiac-hypertrophy-associated piRNA (CHAPIR) that promotes pathological hypertrophy and cardiac remodelling by targeting METTL3-mediated N⁶-methyladenosine (m⁶A) methylation of Parp10 mRNA transcripts. CHAPIR deletion markedly attenuates cardiac hypertrophy and restores heart function, while administration of a CHAPIR mimic enhances the pathological hypertrophic response in pressure-overloaded mice. Mechanistically, CHAPIR–PIWIL4 complexes directly interact with METTL3 and block the m⁶A methylation of Parp10 mRNA transcripts, which upregulates PARP10 expression. The CHAPIR-dependent increase in PARP10 promotes the mono-ADP-ribosylation of GSK3β and inhibits its kinase activity, which results in the accumulation of nuclear NFATC4 and the progression of pathological hypertrophy. Hence, our findings reveal that a piRNA-mediated RNA epigenetic mechanism is involved in the regulation of cardiac hypertrophy and that the CHAPIR–METTL3–PARP10–NFATC4 signalling axis could be therapeutically targeted for treating pathological hypertrophy and maladaptive cardiac remodelling.
... MiRNAs have been profiled in vitro from cell lines using embryoid bodies at different stages of differentiation to model early mouse development 9 . The investigation of small RNAs in vivo during early mammalian development has been relatively limited. ...
Objective:
To detect the expression level of PIWI-interacting RNA in the serum of patients with acute myocardial infarction, and to explore the role of PIWI-interacting RNA in acute myocardial infarction.
Methods:
RNA was extracted from the serum of acute myocardial infarction patients and healthy subjects, and high-throughput sequencing of PIWI-interacting RNAs was performed to screen differentially expressed PIWI-interacting RNAs. Quantitative polymerase chain reaction was used to detect the expression of four differentially expressed PIWI-interacting RNAs in 52 patients with acute myocardial infarction and 30 healthy people. Receiver operating characteristic (ROC) curve was further used to analyze the correlation between differentially expressed PIWI-interacting RNAs and the occurrence of acute myocardial infarction. Kyoto Encyclopedia of Genes and Genomes analysis was used to analyze the role of PIWI-interacting RNA in the occurrence of acute myocardial infarction.
Results:
RNA sequencing and bioinformatics analysis revealed that most piRNAs were upregulated in AMI patients, with 195 upregulated and 13 downregulated. Among them, piR-hsa-9010, piR-hsa-28,646, and piR-hsa-23,619 were significantly up-regulated in the serum of patients with acute myocardial infarction, but their expression in the acute heart failure group and coronary heart disease group was not significantly different from that in the healthy group. ROC curve analysis showed that piR-hsa-9010, piR-hsa-28,646, and piR-hsa-23,619 had high diagnostic values in acute myocardial infarction. In vitro, there was no significant difference in the expression of piR-hsa-9010 among THP-1, HUVEC, and AC16, while the expression of piR-hsa-28,646 and piR-hsa-23,619 in HUVEC was significantly higher than that in THP-1 and AC16. Pathway analysis showed that piR-hsa-23,619 was mainly involved in TNF signaling pathway, and piR-hsa-28,646 was mainly involved in Wnt signaling pathway.
Conclusion:
piR-hsa-9010, piR-hsa-28,646, and piR-hsa-23,619 were significantly up-regulated in the serum of patients with acute myocardial infarction. It can be used as a new biomarker for the diagnosis of acute myocardial infarction, which may be a therapeutic target for acute myocardial infarction.
