MIR137 is the key gene mediator of the syndromic obesity phenotype of patients with 1p21.3 microdeletions

Tucci, Arianna; Ciaccio, Claudia; Scuvera, Giulietta; Esposito, Susanna; Milani, Donatella

doi:10.1186/s13039-016-0289-x

Cited by 13 publications

(14 citation statements)

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“…miR-137 has been linked to various disorders including ID, ASD, and SCZ [ 6 , 10 , 11 , 18 ]. Impaired synaptic plasticity and glutamatergic neurotransmission have been postulated as underlying pathological mechanisms [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…Impaired synaptic plasticity and glutamatergic neurotransmission have been postulated as underlying pathological mechanisms [ 40 ]. A heterozygous microdeletion on 1q21.3 encompassing the genes MIR137 and DPYD was previously described in ID and ASD patients [ 6 , 10 , 11 ]. Reduced levels of precursor and mature miR-137 concurrently with significantly increased levels of downstream target genes ( MITF , EZH2 , and KLF4 ) were determined in lymphoblastoid cells isolated from two patients with this 1q21.3 microdeletion [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…Genetic alterations of MIR137 have been associated with neurodevelopmental disorders. The rare chromosomal microdeletion 1p21.3 encompassing MIR137 and DPYD was identified in individuals with intellectual disability (ID), comorbid with autism spectrum disorder (ASD), and obesity [ 6 , 10 , 11 ]. In addition, 19/65 (29%) highest ranked ASD risk genes in the Simons Foundation Autism Research Initiative gene database [ 12 , 13 ] (URL: https://sfari.org/resources/sfari-gene#refs , accessed May 2017) are predicted or confirmed miR-137 targets (Additional file 1 : Table S1).…”

Section: Introductionmentioning

confidence: 99%

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A direct regulatory link between microRNA-137 and SHANK2: implications for neuropsychiatric disorders

Cortabitarte

Berkel

Cristian

et al. 2018

J Neurodevelop Disord

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BackgroundMutations in the SHANK genes, which encode postsynaptic scaffolding proteins, have been linked to a spectrum of neurodevelopmental disorders. The SHANK genes and the schizophrenia-associated microRNA-137 show convergence on several levels, as they are both expressed at the synapse, influence neuronal development, and have a strong link to neurodevelopmental and neuropsychiatric disorders like intellectual disability, autism, and schizophrenia. This compiled evidence raised the question if the SHANKs might be targets of miR-137.MethodsIn silico analysis revealed a putative binding site for microRNA-137 (miR-137) in the SHANK2 3′UTR, while this was not the case for SHANK1 and SHANK3. Luciferase reporter assays were performed by overexpressing wild type and mutated SHANK2-3′UTR and miR-137 in human neuroblastoma cells and mouse primary hippocampal neurons. miR-137 was also overexpressed or inhibited in hippocampal neurons, and Shank2 expression was analyzed by quantitative real-time PCR and Western blot. Additionally, expression levels of experimentally validated miR-137 target genes were analyzed in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control individuals using the RNA-Seq data from the CommonMind Consortium.ResultsmiR-137 directly targets the 3′UTR of SHANK2 in a site-specific manner. Overexpression of miR-137 in mouse primary hippocampal neurons significantly lowered endogenous Shank2 protein levels without detectable influence on mRNA levels. Conversely, miR-137 inhibition increased Shank2 protein expression, indicating that miR-137 regulates SHANK2 expression by repressing protein translation rather than inducing mRNA degradation.To find out if the miR-137 signaling network is altered in schizophrenia, we compared miR-137 precursor and miR-137 target gene expression in the DLPFC of schizophrenia and control individuals using the CommonMind Consortium RNA sequencing data. Differential expression of 23% (16/69) of known miR-137 target genes was detected in the DLPFC of schizophrenia individuals compared with controls. We propose that in further targets (e.g., SHANK2, as described in this paper) which are not regulated on RNA level, effects may only be detectable on protein level.ConclusionOur study provides evidence that a direct regulatory link exists between miR-137 and SHANK2 and supports the finding that miR-137 signaling might be altered in schizophrenia.Electronic supplementary materialThe online version of this article (10.1186/s11689-018-9233-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A direct regulatory link between microRNA-137 and SHANK2: implications for neuropsychiatric disorders

Cortabitarte

Berkel

Cristian

et al. 2018

J Neurodevelop Disord

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“…Comparably, miR-188-3p upregulation results in the induction of atherosclerosis [236], a disease that has been widely associated with obesity [61]. In regard to miR-137, which is also involved in obesity [237], studies have established that high glucose levels induce dysfunction of human ECs by upregulating miR-137 [238]. This suggests the involvement of miR-137 in the pathogenesis of obesity-induced endothelial dysfunction.…”

Section: Mirnas In the Regulation Of Autophagy Elongationmentioning

confidence: 99%

MicroRNAs and obesity-induced endothelial dysfunction: key paradigms in molecular therapy

Ait‐Aissa¹,

Nguyen²,

Gabani³

et al. 2020

Cardiovasc Diabetol

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The endothelium plays a pivotal role in maintaining vascular health. Obesity is a global epidemic that has seen dramatic increases in both adult and pediatric populations. Obesity perturbs the integrity of normal endothelium, leading to endothelial dysfunction which predisposes the patient to cardiovascular diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that play important roles in a variety of cellular processes such as differentiation, proliferation, apoptosis, and stress response; their alteration contributes to the development of many pathologies including obesity. Mediators of obesity-induced endothelial dysfunction include altered endothelial nitric oxide synthase (eNOS), Sirtuin 1 (SIRT1), oxidative stress, autophagy machinery and endoplasmic reticulum (ER) stress. All of these factors have been shown to be either directly or indirectly caused by gene regulatory mechanisms of miRNAs. In this review, we aim to provide a comprehensive description of the therapeutic potential of miRNAs to treat obesity-induced endothelial dysfunction. This may lead to the identification of new targets for interventions that may prevent or delay the development of obesity-related cardiovascular disease.

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“…The following information on included studies was collected: first author, gene symbol, age of mice, analyzed brain region, test platform, database, and project number. With all above, the major clinical information related to these mutant genes was collected from OMIM database and several reviews [Carratala-Marco et al, 2018;D'Angelo, Moller, Alonso, & Koiffmann, 2015;Geets, Meuwissen, & Van Hul, 2019;Merner et al, 2016;Tucci, Ciaccio, Scuvera, Esposito, & Milani, 2016].…”

Section: Identification Of Literature and Collection Of Informationmentioning

confidence: 99%

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

et al. 2019

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Genetic mutations are the major pathogenic factor of Autism Spectrum Disorder (ASD). In recent years, more and more ASD risk genes have been revealed, among which there are a group of transcriptional regulators. Considering the similarity of the core clinical phenotypes, it is possible that these different factors may regulate the expression levels of certain key targets. Identification of these targets could facilitate the understanding of the etiology and developing of novel diagnostic and therapeutic methods. Therefore, we performed integrated transcriptome analyses of RNA‐Seq and microarray data in multiple ASD mouse models and identified a number of common downstream genes in various brain regions, many of which are related to the structure and function of the synapse components or drug addiction. We then established protein–protein interaction networks of the overlapped targets and isolated the hub genes by 11 algorithms based on the topological structure of the networks, including Sdc4, Vegfa, and Cp in the Cortex‐Adult subgroup, Gria1 in the Cortex‐Juvenile subgroup, and Kdr, S1pr1, Ubc, Grm2, Grin2b, Nrxn1, Pdyn, Grin3a, Itgam, Grin2a, Gabra2, and Camk4 in the Hippocampus‐Adult subgroup, many of which have been associated with ASD in previous studies. Finally, we cross compared our results with human brain transcriptional data sets and verified several key candidates, which may play important role in the pathology process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRIN2A, GABRA2, and CAMK4. In summary, by integrated bioinformatics analysis, we have identified a series of potentially important molecules for future ASD research. Autism Res 2020, 13: 352–368. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Abnormal transcriptional regulation accounts for a significant portion of Autism Spectrum Disorder. In this study, we performed transcriptome analyses of mouse models to identify common downstream targets of transcriptional regulators involved in ASD. We identified several recurrent target genes that are close related to the common pathological process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRM2, NRXN1, GRIN3A, ITGAM, GRIN2A, GABRA2, and CAMK4. These results provide potentially important targets for understanding the molecular mechanism of ASD.

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MIR137 is the key gene mediator of the syndromic obesity phenotype of patients with 1p21.3 microdeletions

Cited by 13 publications

References 32 publications

A direct regulatory link between microRNA-137 and SHANK2: implications for neuropsychiatric disorders

A direct regulatory link between microRNA-137 and SHANK2: implications for neuropsychiatric disorders

MicroRNAs and obesity-induced endothelial dysfunction: key paradigms in molecular therapy

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

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