scholarly journals Gene of the month: DICER1: ruler and controller

2020 ◽  
pp. jclinpath-2020-207203
Author(s):  
Michelle Thunders ◽  
Brett Delahunt
Keyword(s):  
Critical Role ◽  
Transcriptional Gene Silencing ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Malignant Tumours ◽  
Protein Coding ◽  
Post Transcriptional Gene Silencing ◽  
Small Regulatory Rnas ◽  
Dicer1 Syndrome ◽  
Novel Therapeutic Strategies

DICER1 is a highly conserved RNaseIII endoribonuclease that has a critical role in the biogenesis of microRNAs (miRNAs). miRNAs are small regulatory RNAs responsible for post-transcriptional gene silencing, controlling more than half of human protein-coding genes. This is achieved through the targeting and regulation of complementary RNA transcripts and has a well-documented role in post-transcriptional gene regulation and transposon repression. DICER1 deficiency results in dysregulation of miRNAs, changing the expression of many genes. DICER1 syndrome represents a collection of benign and malignant tumours arising from an autosomally inherited germline mutation leading to an inherited predisposition to cancer. The syndrome represents an unusual form of Knudson’s two-hit hypothesis, where individuals with a pathogenic germline DICER1 variant acquire a second trans-somatic missense DICER1 mutation. This somatic mutation appears to have to occur in one of five hotspots codons and may contribute towards the incomplete penetrance observed within DICER1 syndrome families. In this case, DICER1 is haploinsuffcient with only one deletion required and partial loss of function being advantageous to tumours over complete loss of function. As increasing data emerge reaffirming the pivotal role of DICER1 in the maintenance of human physiology, DICER1 is likely to become an increasingly attractive target for novel therapeutic strategies.

scholarly journals Cancer-Derived Extracellular Vesicle-Associated MicroRNAs in Intercellular Communication: One Cell’s Trash Is Another Cell’s Treasure

2019 ◽  
Vol 20 (24) ◽  
pp. 6109 ◽  
Author(s):  
Joseph Mills ◽  
Marina Capece ◽  
Emanuele Cocucci ◽  
Anna Tessari ◽  
Dario Palmieri
Keyword(s):  
Intercellular Communication ◽  
Critical Role ◽  
Genetic Material ◽  
Cell Types ◽  
Extracellular Vesicle ◽  
Transcriptional Gene Silencing ◽  
Protein Coding ◽  
Cancer Pathogenesis ◽  
Post Transcriptional Gene Silencing ◽  
Genomic Regions

Several non-protein-coding genomic regions, previously marked as “junk DNA”, have been reported to be transcriptionally active, giving rise to non-coding RNA species implicated in fundamental biological and pathological processes. In particular, microRNAs (miRNAs), a class of small non-coding RNAs mediating post-transcriptional gene silencing, are causally involved in several human diseases, including various cancer types. Extracellular vesicles (EVs) are membranous structures physiologically released by most cell types. Initially, they were considered a “waste-removal” mechanism, through which cells could dispose unnecessary material and organelles. It is now widely demonstrated that EVs also play a critical role in intercellular communication, mediating the horizontal transfer of lipids, proteins, and genetic material. A paradigm shift in the biology of miRNAs was represented by the discovery that EVs, especially from cancer cells, contain miRs. EV-associated miRs act as autocrine, paracrine and endocrine factors, participating in cancer pathogenesis by modulating intercellular communication. Noteworthy, these formerly neglected molecules are now considered the next generation of cancer “theranostic” tools, with strong clinical relevance. In this review, we aim to summarize the most recent findings regarding EV-associated miRs in cancer pathogenesis and in the development of novel anti-neoplastic diagnostic and therapeutic approaches.

scholarly journals MicroRNAs in Cardiac Autophagy: Small Molecules and Big Role

Cells ◽  
2018 ◽  
Vol 7 (8) ◽  
pp. 104 ◽  
Author(s):  
Teng Sun ◽  
Meng-Yang Li ◽  
Pei-Feng Li ◽  
Ji-Min Cao
Keyword(s):  
Cardiac Fibrosis ◽  
Heart Diseases ◽  
Critical Role ◽  
Transcriptional Gene Silencing ◽  
Close Link ◽  
Post Transcriptional Gene Silencing ◽  
Evolutionarily Conserved ◽  
Cardiac Disorders ◽  
Cellular Components

Autophagy, which is an evolutionarily conserved process according to the lysosomal degradation of cellular components, plays a critical role in maintaining cell homeostasis. Autophagy and mitochondria autophagy (mitophagy) contribute to the preservation of cardiac homeostasis in physiological settings. However, impaired or excessive autophagy is related to a variety of diseases. Recently, a close link between autophagy and cardiac disorders, including myocardial infarction, cardiac hypertrophy, cardiomyopathy, cardiac fibrosis, and heart failure, has been demonstrated. MicroRNAs (miRNAs) are a class of small non-coding RNAs with a length of approximately 21–22 nucleotides (nt), which are distributed widely in viruses, plants, protists, and animals. They function in mediating the post-transcriptional gene silencing. A growing number of studies have demonstrated that miRNAs regulate cardiac autophagy by suppressing the expression of autophagy-related genes in a targeted manner, which are involved in the pathogenesis of heart diseases. This review summarizes the role of microRNAs in cardiac autophagy and related cardiac disorders. Furthermore, we mainly focused on the autophagy regulation pathways, which consisted of miRNAs and their targeted genes.

scholarly journals Dual-layer transposon repression in heads of Drosophila melanogaster

2018 ◽  
Author(s):  
Marius van den Beek ◽  
Bruno da Silva ◽  
Juliette Pouch ◽  
Mohammed el amine Ali Chaouche ◽  
Clément Carré ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Gene Silencing ◽  
Rna Extraction ◽  
Transcript Abundance ◽  
Transcriptional Gene Silencing ◽  
Loss Of Function ◽  
Wild Type ◽  
Rna Molecules ◽  
Post Transcriptional Gene Silencing ◽  
Ping Pong

AbstractpiRNA-mediated repression of transposable elements (TE) in the germline limits the accumulation of heritable mutations caused by their transposition in the genome. It is not clear whether the piRNA pathway plays a functional role in adult, non-gonadal tissues in Drosophila melanogaster. To address this question, we first analyzed the small RNA content of adult Drosophila melanogaster heads. We found that varying amount of piRNA-sized, ping-pong positive molecules in heads correlates with contamination by gonadal tissue during RNA extraction, suggesting that most of piRNAs detected in head sequencing libraries originate from gonads. We next sequenced the heads of wild type and piwi mutants to address whether piwi loss of function would affect the low amount of piRNA-sized, ping-pong negative molecules that are still detected in heads hand-checked to avoid gonadal contamination. We find that loss of piwi does not affect significantly these 24-28 RNA molecules. Instead, we observe increased siRNA levels against the majority of Drosophila transposable element families. To determine the effect of this siRNA level change on transposon expression, we sequenced the transcriptome of wild type, piwi, dicer-2 and piwi, dicer-2 double-mutant fly heads. We find that RNA expression levels of the majority of TE families in piwi or dicer-2 mutants remain unchanged and that TE transcript abundance increases significantly only in piwi, dicer-2 double-mutants. These results lead us to suggest a dual-layer model for TE repression in adult somatic tissues. Piwi-mediated transcriptional gene silencing (TGS) established during embryogenesis constitutes the first layer of TE repression whereas Dicer-2-dependent siRNA-mediated post-transcriptional gene silencing (PTGS) provide a backup mechanism to repress TEs that escape silencing by piwi-mediated TGS.

scholarly journals Plant Polymerase IV sensitizes chromatin through histone modifications to preclude spread of silencing into protein-coding domains

2021 ◽  
Author(s):  
Vivek H Sundar ◽  
Chenna Swetha ◽  
Debjani Basu ◽  
Kannan Pachamuthu ◽  
Tania Chakraborty ◽  
...  
Keyword(s):  
Small Rnas ◽  
Transcriptional Activity ◽  
Constitutive Heterochromatin ◽  
Division Of Labour ◽  
Transcriptional Gene Silencing ◽  
Protein Coding ◽  
Heterochromatin Formation ◽  
Protein Coding Genes ◽  
Post Transcriptional Gene Silencing ◽  
Architectural Feature

Heterochromatin is the predominant architectural feature of genomes that ensures genomic stability across eukaryotes. It mostly functions in restricting expression of repeats, mobile elements such as transposons and other regions. The establishment, maintenance and spreading of heterochromatin requires several factors including chromatin modifiers. However, how exactly heterochromatin formation is avoided in protein-coding domains is poorly understood. Here we show that a plant specific paralogue of RNA polymerase (pol) II, named pol IV, is involved in avoidance of facultative heterochromatic marks in protein coding genes, in addition to silencing the repeats and transposons forming constitutive heterochromatin. In its absence, H3K27 trimethylation mark intrudes the protein coding genes, more profoundly in genes embedded with repeats. In a subset of genes that lack the compensatory silencing, spurious transcriptional activity results in small(s)RNA production leading to post-transcriptional gene silencing. We show that such effects are significantly pronounced in rice, a plant with larger genome with distributed heterochromatin when compared to Arabidopsis. Our results indicate the surprising division of labour among plant-specific polymerases, not just in establishing effective silencing via small RNAs and epigenetics, but also in influencing chromatin boundaries.

scholarly journals Heterozygous gene truncation delineates the human haploinsufficient genome

2014 ◽  
Author(s):  
István Bartha ◽  
Antonio Rausell ◽  
Paul McLaren ◽  
Manuel Tardaguila ◽  
Pejman Mohammadi ◽  
...  
Keyword(s):  
De Novo ◽  
De Novo Mutation ◽  
Phenotypic Traits ◽  
Incomplete Penetrance ◽  
Heterozygous State ◽  
Loss Of Function ◽  
Protein Coding ◽  
Large Numbers ◽  
Human Genes ◽  
Compensatory Mutations

Sequencing projects have identified large numbers of rare stop-gain and frameshift variants in the human genome. As most of these are observed in the heterozygous state, they test a gene?s tolerance to haploinsufficiency and dominant loss of function. We analyzed the distribution of truncating variants across 16,260 protein coding autosomal genes in 11,546 individuals. We observed 39,893 truncating variants affecting 12,062 genes, which significantly differed from an expectation of 12,916 genes under a model of neutral de novo mutation (p<1E-4). Extrapolating this to increasing numbers of sequenced individuals, we estimate that 10.8% of human genes do not tolerate heterozygous truncating variants. An additional 10 to 15% of truncated genes may be rescued by incomplete penetrance or compensatory mutations, or because the truncating variants are of limited functional impact. The study of protein truncating variants delineates the essential genome and, more generally, identifies rare heterozygous variants as an unexplored source of diversity of phenotypic traits and diseases.

scholarly journals MicroRNA840 accelerates leaf senescence by targeting the overlapping 3’UTRs of PPR and WHIRLY3 in Arabidopsis thaliana

2020 ◽  
Author(s):  
Ren Yujun ◽  
Wang Wanzhen ◽  
Lan Wei ◽  
Schenke Dirk ◽  
Cai Daguang ◽  
...  
Keyword(s):  
Stress Responses ◽  
Transcript Level ◽  
Transcriptional Gene Silencing ◽  
Loss Of Function ◽  
Knockout Mutant ◽  
Plant Senescence ◽  
Senescent Phenotype ◽  
Post Transcriptional Gene Silencing

AbstractMicroRNAs (miRNAs) negatively regulate gene expression by cleaving the target mRNA and/or impairing its translation, thereby playing a crucial role in plant development and environmental stress responses. In Arabidopsis, MIR840 is located within the overlapping 3’UTR of PPR and WHIRLY3 (WHY3), both being predicted targets of miR840. Gain- and loss-of-function of miR840 in Arabidopsis resulted in opposite senescent phenotypes. Highest expression of pri-miR840 is observed at senescence initiation, and is negatively correlated with a significant reduction of PPR transcripts but not of WHY3. Although WHY3 transcript levels were not significantly affected by miR840 overexpression, its protein synthesis was strongly reduced. Mutating the cleavage sites or replacing the target sequences abolishes the miR840-mediated degradation of PPR transcripts and inhibition of WHY3 translation. In support for this, concurrent knock-down of both PPR and WHY3 in the WT resulted in the senescent phenotype resembling that of the miR840-overexpressing mutant. This indicates that both PRR and WHY3 are targets in the miR840-regulated senescent pathway. Moreover, single knockout mutant of PPR or WHY3 shows a convergent up-regulated subset of senescence-associated genes, which are also found among those induced by miR840 overexpression. Our data provide evidences for a regulatory role of miR840 in plant senescence.HighlightMicroRNA840 (miR840) has a unique miRNA-target configuration regulating PPR and WHIRLY3 genes in Arabidopsis. MiR840 is highly expressed at the onset of plant senescent stage. Both PPR and WHIRLY3 transcripts are specifically targeted in vivo within their 3’UTR region by mature miR840 or its star strand in vivo. Interestingly, PPR expression is mainly repressed on mRNA transcript level by cleavage, while WHIRLY3 is predominantly translationally inhibited. We conclude that miR840 enhances plant senescence via post transcriptional gene silencing of PPR and WHIRLY3, which appear to be novel negative joint regulators of plant senescence.Footnote: The author(s) responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the intructions for Authors is: Ying Miao ([email protected])

scholarly journals A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Joanne M. Hildebrand ◽  
Bernice Lo ◽  
Sara Tomei ◽  
Valentina Mattei ◽  
Samuel N. Young ◽  
...  
Keyword(s):  
Potential Role ◽  
Autosomal Dominant ◽  
Inflammatory Diseases ◽  
Diabetic Patients ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Healthy Sibling ◽  
Dominant Disease ◽  
Terminal Effector

AbstractMaturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.

scholarly journals LINC01089 functions as a ceRNA for miR-152-3p to inhibit non‐small lung cancer progression through regulating PTEN

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Huixian Zhang ◽  
Hao Zhang ◽  
Xingya Li ◽  
Siyuan Huang ◽  
Qianqian Guo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Expression Level ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Protein Coding ◽  
Tensin Homolog ◽  
Pten Mrna

Abstract Background Long non-coding RNAs (lncRNAs) have been reported to exert crucial functions in regulating the progression of human cancers. However, the function and mechanism of long intergenic non-protein coding RNA 01089 (LINC01089) in non-small cell lung cancer (NSCLC) have not been revealed. Methods The expression level of LINC01089, microRNA (miRNA, miR)-152-3p and phosphatase and tensin homolog deleted onc hromosome ten (PTEN) mRNA was detected by quantitative real-time PCR (qRT-PCR). After gain-of-function and loss-of-function models were established with NSCLC cell lines, the proliferation, migration and invasion of NSCLC cells were detected by cell counting kit-8 (CCK-8) assay, scratch healing assay, Transwell assay, respectively. Dual luciferase reporter assay was employed to validate the binding relationship between miR-152-3p and LINC01089 or the 3’UTR of PTEN. Western blot was used to detect PTEN expression in NSCLC cells after LINC01089 and miR-152-3p were selectively modulated. Results LINC01089 was down-regulated in NSCLC tissues and cells. Functional experiments showed that knockdown of LINC01089 could promote the proliferation, migration and invasion of NSCLC cells, while over-expression of LINC01089 had the opposite effects. miR-152-3p was identified as a functional target for LIN01089, and miR-152-3p could reverse the function of LINC01089. Additionally, LINC01089 could up-regulate the expression level of PTEN via repressing miR-152-3p. Conclusions Down-regulation of LINC01089 promoted the progression of NSCLC through regulating miR-152-3p/PTEN axis.

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