Tissue-specific and transcription-dependent mechanisms regulate primary microRNA processing efficiency of the human chromosome 19 MicroRNA cluster

Fóthi, Ábel; Bíró, Orsolya; Erdei, Zsuzsa; Apáti, Ágota; Orbán, Tamás I.

doi:10.1080/15476286.2020.1836457

Cited by 8 publications

(9 citation statements)

References 52 publications

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“…Fothi et al described an epigenetically regulated placental tissue-specific promoter, which is silenced in stem cells. This promoter is particularly efficient in attracting the transcription protein complex that optimizes cluster expression [ 56 ]. C19MC miRNAs are transcribed by RNA polymerase II and are processed from introns of a poorly characterized transcript, C19MC-HG (host gene), composed of many repeated non-coding exons [ 57 ].…”

Section: Micrornasmentioning

confidence: 99%

“…Malnou et al raised the question whether some miRNAs of C19MC sharing the same seed sequence may have related mRNA targets (or families thereof), perhaps underlying similar functions [ 49 ]. However, this question should also reflect the field of biomarker research, focusing perhaps on quantification of a panel of miRNAs with the same seed sequence or targets, especially taking into account that miRNAs from the C19MC cluster originate from the one large pre-miRNA transcript, and that the main regulation is its transcription [ 50 , 56 , 57 ].…”

Section: Micrornasmentioning

confidence: 99%

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Non-Coding RNAs in Preeclampsia—Molecular Mechanisms and Diagnostic Potential

Munjas

Sopić

Stefanović

et al. 2021

IJMS

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Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity and mortality worldwide. Defects in trophoblast invasion, differentiation of extravillous trophoblasts and spiral artery remodeling are key factors in PE development. Currently there are no predictive biomarkers clinically available for PE. Recent technological advancements empowered transcriptome exploration and led to the discovery of numerous non-coding RNA species of which microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the most investigated. They are implicated in the regulation of numerous cellular functions, and as such are being extensively explored as potential biomarkers for various diseases. Altered expression of numerous lncRNAs and miRNAs in placenta has been related to pathophysiological processes that occur in preeclampsia. In the following text we offer summary of the latest knowledge of the molecular mechanism by which lnRNAs and miRNAs (focusing on the chromosome 19 miRNA cluster (C19MC)) contribute to pathophysiology of PE development and their potential utility as biomarkers of PE, with special focus on sample selection and techniques for the quantification of lncRNAs and miRNAs in maternal circulation.

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Section: Micrornasmentioning

confidence: 99%

Section: Micrornasmentioning

confidence: 99%

Non-Coding RNAs in Preeclampsia—Molecular Mechanisms and Diagnostic Potential

Munjas

Sopić

Stefanović

et al. 2021

IJMS

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“…The considerable decrease in DGCR8 protein levels prompted us to test whether the activity or any functions related to the Microprocessor complex are disturbed in the examined cell clones. In a recent study, we showed that the depletion of Drosha in hESCs caused a gradual decrease in pri-miRNA processing along an extended miRNA cluster, C19MC [ 14 ]. We also proposed that depleting DGCR8, the other component of the Microprocessor complex, may result in a similar phenotype; therefore, we tested the processing activity in three selected regions of C19MC in the four DGCR8 heterozygous clones.…”

Section: Resultsmentioning

confidence: 99%

“…The chromosome 19 miRNA cluster (C19MC) is an especially long (46 miRNA genes) cluster predominantly expressed in human embryonic stem cells (hESCs) and in the reproductive system. In hESCs, the position-dependent processing of this cluster is regulated by the Microprocessor recruitment, explaining why the miRNA expression levels in the Drosha knockdown of those cells gradually decrease toward the 3′ end of the cluster [ 14 ]. To further explore the molecular mechanisms behind this phenomenon, the recruitment and role of DGCR8 or additional Microprocessor-associated factors also need to be studied.…”

Section: Introductionmentioning

confidence: 99%

Partial Disturbance of Microprocessor Function in Human Stem Cells Carrying a Heterozygous Mutation in the DGCR8 Gene

Reé

Fóthi

Varga

et al. 2022

Genes

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Maturation of microRNAs (miRNAs) begins by the “Microprocessor” complex, containing the Drosha endonuclease and its partner protein, "DiGeorge Syndrome Critical Region 8" (DGCR8). Although the main function of the two proteins is to coordinate the first step of precursor miRNAs formation, several studies revealed their miRNA-independent functions in other RNA-related pathways (e.g., in snoRNA decay) or, for the DGCR8, the role in tissue development. To investigate the specific roles of DGCR8 in various cellular pathways, we previously established a human embryonic stem-cell (hESC) line carrying a monoallelic DGCR8 mutation by using the CRISPR-Cas9 system. In this study, we genetically characterized single-cell originated progenies of the cell line and showed that DGCR8 heterozygous mutation results in only a modest effect on the mRNA level but a significant decrease at the protein level. Self-renewal and trilineage differentiation capacity of these hESCs were not affected by the mutation. However, partial disturbance of the Microprocessor function could be revealed in pri-miRNA processing along the human chromosome 19 miRNA cluster in several clones. With all these studies, we can demonstrate that the mutant hESC line is a good model to study not only miRNA-related but also other “noncanonical” functions of the DGCR8 protein.

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“…They form clusters on some chromosomes, representative of which are the chromosome 19 miRNA cluster (C19MC), chromosome 14 miRNA cluster (C14MC), and miR-371-3 cluster [ 63 ]. C19MC is an approximately 100-kb-long imprinted gene cluster located on 19q13.41 and consists of 46 miRNAs expressed only from the paternally inherited chromosome [ 63 , 64 ]. Using microarray analysis and RT-PCR validation, Morales–Prieto et al showed that C19MC miRNAs were highly expressed in the early placenta, with further increases being observed with the progression of pregnancy [ 51 ].…”

Section: Highly Expressed Ncrnas In the First Trimester Placentamentioning

confidence: 99%

Non-Coding RNAs and Prediction of Preeclampsia in the First Trimester of Pregnancy

Ogoyama

Takahashi

Suzuki

et al. 2022

Cells

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Preeclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality. The only fundamental treatment for PE is the termination of pregnancy. Therefore, not only severe maternal complications but also perinatal complications due to immaturity of the infant associated with early delivery are serious issues. The treatment and prevention of preterm onset preeclampsia (POPE) are challenging. In 2017, the ASPRE trial showed that a low oral dose of aspirin administered to POPE high-risk women in early pregnancy reduced POPE by 62%. A prediction algorithm at 11–13 weeks of gestation identifies POPE with 75% sensitivity when the false positive rate is set at 10%. New biomarkers to increase the accuracy of the prediction model for POPE high-risk women in early pregnancy are needed. In this review, we focused on non-coding RNAs (ncRNAs) as potential biomarkers for the prediction of POPE. Highly expressed ncRNAs in the placenta in early pregnancy may play crucial roles in placentation. Furthermore, placenta-specific ncRNAs have been detected in maternal blood. In this review, we summarized ncRNAs that were highly expressed in the primary human placenta in early pregnancy. We also presented highly expressed ncRNAs in the placenta that were associated with or predictive of the development of PE in an expression analysis of maternal blood during the first trimester of pregnancy. These previous studies showed that the chromosome 19 microRNA (miRNA) -derived miRNAs (e.g., miR-517-5p, miR-518b, and miR-520h), the hypoxia-inducible miRNA (miR-210), and long non-coding RNA H19, were not only highly expressed in the early placenta but were also significantly up-regulated in the blood at early gestation in pregnant women who later developed PE. These maternal circulating ncRNAs in early pregnancy are expected to be possible biomarkers for POPE.

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Tissue-specific and transcription-dependent mechanisms regulate primary microRNA processing efficiency of the human chromosome 19 MicroRNA cluster

Cited by 8 publications

References 52 publications

Non-Coding RNAs in Preeclampsia—Molecular Mechanisms and Diagnostic Potential

Non-Coding RNAs in Preeclampsia—Molecular Mechanisms and Diagnostic Potential

Partial Disturbance of Microprocessor Function in Human Stem Cells Carrying a Heterozygous Mutation in the DGCR8 Gene

Non-Coding RNAs and Prediction of Preeclampsia in the First Trimester of Pregnancy

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