Wnt signalling mediates miR-133a nuclear re-localization for the transcriptional control of Dnmt3b in cardiac cells

Mauro, Vittoria Di; Crasto, Silvia; Colombo, Federico; Pasquale, Elisa Di; Catalucci, Daniele

doi:10.1038/s41598-019-45818-4

Cited by 33 publications

(23 citation statements)

References 66 publications

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“…C-Score-Combined Annotation Dependent Depletion (CADD) score is a broadly applicable metric that objectively weights and integrates diverse information that integrates multiple functional annotations into one metric by contrasting variants that survived natural selection with simulated mutations. has not yet been demonstrated, it has been shown that inactivated canonical WNT signaling facilitated nuclear entry of miR-133a and complexed with AGO2 to suppress DnmT3b expression in mouse HL-1 cells 50 . Also, the presence of p.Y544C impaired LRP6 localization to plasma membrane for facilitating WNT signaling 42 .…”

Section: Discussionmentioning

confidence: 97%

Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

Au¹,

Hebert²,

Hillman³

et al. 2021

Sci Rep

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Myelomeningocele (MMC) affects one in 1000 newborns annually worldwide and each surviving child faces tremendous lifetime medical and caregiving burdens. Both genetic and environmental factors contribute to disease risk but the mechanism is unclear. This study examined 506 MMC subjects for ultra-rare deleterious variants (URDVs, absent in gnomAD v2.1.1 controls that have Combined Annotation Dependent Depletion score ≥ 20) in candidate genes either known to cause abnormal neural tube closure in animals or previously associated with human MMC in the current study cohort. Approximately 70% of the study subjects carried one to nine URDVs among 302 candidate genes. Half of the study subjects carried heterozygous URDVs in multiple genes involved in the structure and/or function of cilium, cytoskeleton, extracellular matrix, WNT signaling, and/or cell migration. Another 20% of the study subjects carried heterozygous URDVs in candidate genes associated with gene transcription regulation, folate metabolism, or glucose metabolism. Presence of URDVs in the candidate genes involving these biological function groups may elevate the risk of developing myelomeningocele in the study cohort.

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Section: Discussionmentioning

confidence: 97%

Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

Au¹,

Hebert²,

Hillman³

et al. 2021

Sci Rep

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show abstract

“…Increasing evidence shows that this is true. For instance, several miRNAs that are prominently localized in the nucleus have been associated with transcriptional regulation [144]. Many miRNA-binding sites in gene promoters in sense and antisense orientations have been predicted by in silico analyses [145].…”

Section: Mirna-mediated Transcriptional Regulationmentioning

confidence: 99%

“…Another example of miRNA-mediated DNA methylation is described for miR-133a. The promoter of Dnmt3b contains a miR-133a binding site in pluripotent stem cells [144]. The interaction of miR-133a with the promoter of Dnmt3b recruits DNMT3B via direct binding to AGO2.…”

Section: Mirna-mediated Transcriptional Regulationmentioning

confidence: 99%

The Non-Canonical Aspects of MicroRNAs: Many Roads to Gene Regulation

Stavast

Erkeland

2019

Cells

313

207

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MicroRNAs (miRNAs) are critical regulators of gene expression. As miRNAs are frequently deregulated in many human diseases, including cancer and immunological disorders, it is important to understand their biological functions. Typically, miRNA-encoding genes are transcribed by RNA Polymerase II and generate primary transcripts that are processed by RNase III-endonucleases DROSHA and DICER into small RNAs of approximately 21 nucleotides. All miRNAs are loaded into Argonaute proteins in the RNA-induced silencing complex (RISC) and act as post-transcriptional regulators by binding to the 3′- untranslated region (UTR) of mRNAs. This seed-dependent miRNA binding inhibits the translation and/or promotes the degradation of mRNA targets. Surprisingly, recent data presents evidence for a target-mediated decay mechanism that controls the level of specific miRNAs. In addition, several non-canonical miRNA-containing genes have been recently described and unexpected functions of miRNAs have been identified. For instance, several miRNAs are located in the nucleus, where they are involved in the transcriptional activation or silencing of target genes. These epigenetic modifiers are recruited by RISC and guided by miRNAs to specific loci in the genome. Here, we will review non-canonical aspects of miRNA biology, including novel regulators of miRNA expression and functions of miRNAs in the nucleus.

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“…Function of tsRNAs binding to Argonaute (AGO) protein is similar to miRNAs [23]. Binding of nuclear miRNAs to promoters leads to activate [24][25][26] or silence [27][28][29] the transcription of target genes. Therefore, we speculate that tsRNAs are similar to miRNAs and play a regulatory role through targeting promoters.…”

Section: Construction Of Tsrna-promoter Interaction Networkmentioning

confidence: 99%

Integrated Analysis of tRNA-Derived Small RNAs in Proliferative Human Aortic Smooth Muscle Cells

Zhao

Lin

Gong

et al. 2021

Preprint

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Background Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling diseases. Recently, it has been discovered that tRNA-derived small RNAs (tsRNAs), a new type of non-coding RNAs, are related to the proliferation and migration of VSMCs. tsRNAs regulate target gene expression through miRNA-like function. This study aims to explore the potential of tsRNAs in human aortic smooth muscle cell (HASMC) proliferation. Methods High-throughput sequencing was performed to analyze the tsRNA expression profile of proliferative and quiescent HASMCs. Quantitative real-time PCR (qRT-PCR) was performed to validate sequence results and subcellular distribution of AS-tDR-001370, AS-tDR-000067, AS-tDR-009512, and AS-tDR-000076. Based on microRNA-like functions of tsRNAs, we predicted target promoters, mRNAs, and circular RNAs (circRNAs), constructed tsRNA-promoter, tsRNA-mRNA, and circRNA-tsRNA interaction networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to reveal the function of target genes. Western blot and EdU incorporation assays were utilized to detect the effect of tsRNAs on HASMC proliferation. Results Compared with quiescent HASMCs, 887 up-regulated and 951 down-regulated tsRNAs in proliferative HASMCs were identified (fold change > 2 or < -2, p‑value < 0.05). AS-tDR-001370, AS-tDR-000067, AS-tDR-009512, and AS-tDR-000076 were up-regulated in proliferative HASMCs and were mainly located in the nucleus. Bioinformatics analysis suggested that they involve a variety of terms and pathways related to VSMC proliferation. Knockdown of AS-tDR-000067 promoted the expression of target gene p53 and inhibited HASMC proliferation. Knockdown of AS-tDR-000076 promoted the expression of target gene mitofusin 2 (MFN2) and inhibited HASMC proliferation. Conclusion During HASMC proliferation, the expression levels of many tsRNAs are altered. AS-tDR-000067 and AS-tDR-000076 may become a new therapeutic target for vascular remodeling diseases.

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Wnt signalling mediates miR-133a nuclear re-localization for the transcriptional control of Dnmt3b in cardiac cells

Cited by 33 publications

References 66 publications

Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

The Non-Canonical Aspects of MicroRNAs: Many Roads to Gene Regulation

Integrated Analysis of tRNA-Derived Small RNAs in Proliferative Human Aortic Smooth Muscle Cells

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