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1
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Imura T, Abiko M, Tanaka R. Bioinformatic Exploration of Circulating microRNAs Related to Functional Outcomes in Patients With Acute Ischemic Stroke: An Exploratory Prospective Study. Cureus 2024; 16:e67476. [PMID: 39310540 PMCID: PMC11415936 DOI: 10.7759/cureus.67476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2024] [Indexed: 09/25/2024] Open
Abstract
Background Although epigenetic modifications have been expected to play an important role in neuroplasticity for stroke recovery, the role of dynamic microRNA (miRNA) regulation related to functional outcomes after ischemic stroke remains unclear. Therefore, the current study performed a comprehensive miRNA expression analysis in serum to identify specifically altered circulating miRNAs associated with different grades of functional outcomes in patients with acute ischemic stroke (AIS). Methods Twelve patients with AIS in the middle cerebral artery region were included in this study. Peripheral blood samples were collected from patients one or two days after hospitalization. Total RNA, including small RNAs, was extracted from 400 µL of serum, and comprehensive miRNA expression analysis was performed to identify specifically altered circulating miRNAs associated with different grades of functional outcomes. Functional outcomes were evaluated three months after stroke onset using the modified Rankin Scale (mRS), classified as favorable (mRS score of 0 or 1) or unfavorable (mRS score of 2 to 5). Differentially expressed miRNAs were analyzed using the DESeq2 package. Target genes of the miRNAs were explored using miRTargetLink 2.0. Results Acute miRNA expression dynamics were characterized by differences in the patients' functional outcomes following ischemic stroke. The favorable outcome group exhibited significantly downregulated miRNAs, including hsa-miR-218-1, hsa-miR-218-2, hsa-miR-320e, hsa-miR-320d-1, hsa-miR-320d-2, hsa-miR-326, and hsa-miR-4429. In addition, 15 miRNAs, including hsa-miR-223, hsa-miR-18a, hsa-miR-411, and hsa-miR-128-1, were significantly upregulated in the favorable outcome group compared to the unfavorable outcome group. Interesting and strong validated networks between miRNAs and their target genes were identified. Conclusion This study identified specifically altered circulating miRNAs in serum associated with varying grades of functional outcomes in AIS patients and explored miRNA-target gene networks that might contribute to these outcomes. Although further studies are needed, this study highlights their potential role as biomarkers for predicting functional outcomes in patients with AIS.
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Affiliation(s)
- Takeshi Imura
- Department of Rehabilitation, Hiroshima Cosmopolitan University, Hiroshima, JPN
| | - Masaru Abiko
- Department of Neurosurgery, JA Onomichi General Hospital, Onomichi, JPN
| | - Ryo Tanaka
- Graduate School of Humanities and Social Sciences, Hiroshima University, Higashihiroshima, JPN
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2
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Margiana R, Kzar HH, Hussam F, Hameed NM, Al-Qaim ZH, Al-Gazally ME, Kandee M, Saleh MM, Toshbekov BBU, Tursunbaev F, Karampoor S, Mirzaei R. Exploring the impact of miR-128 in inflammatory diseases: A comprehensive study on autoimmune diseases. Pathol Res Pract 2023; 248:154705. [PMID: 37499519 DOI: 10.1016/j.prp.2023.154705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 07/19/2023] [Accepted: 07/19/2023] [Indexed: 07/29/2023]
Abstract
microRNAs (miRNAs) play a crucial role in various biological processes, including immune system regulation, such as cell proliferation, tolerance (central and peripheral), and T helper cell development. Dysregulation of miRNA expression and activity can disrupt immune responses and increase susceptibility to neuroimmune disorders. Conversely, miRNAs have been shown to have a protective role in modulating immune responses and preventing autoimmunity. Specifically, reducing the expression of miRNA-128 (miR-128) in an Alzheimer's disease (AD) mouse model has been found to improve cognitive deficits and reduce neuropathology. This comprehensive review focuses on the significance of miR-128 in the pathogenesis of neuroautoimmune disorders, including multiple sclerosis (MS), AD, Parkinson's disease (PD), Huntington's disease (HD), epilepsy, as well as other immune-mediated diseases such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). Additionally, we present compelling evidence supporting the potential use of miR-128 as a diagnostic or therapeutic biomarker for neuroimmune disorders. Collectively, the available literature suggests that targeting miR-128 could be a promising strategy to alleviate the behavioral symptoms associated with neuroimmune diseases. Furthermore, further research in this area may uncover new insights into the molecular mechanisms underlying these disorders and potentially lead to the development of novel therapeutic approaches.
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Affiliation(s)
- Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Hamzah H Kzar
- Veterinary Medicine College, Al-Qasim Green University, Al-Qasim, Iraq
| | - Fadhil Hussam
- College of Medical Technology, Medical Lab Techniques, Al-farahidi University, Iraq
| | - Noora M Hameed
- Anesthesia Techniques, Al-Nisour University College, Iraq
| | | | | | - Mahmoud Kandee
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Hofuf 31982, Al-Ahsa, Saudi Arabia; Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelshikh University, Kafrelshikh 33516, Egypt
| | - Marwan Mahmood Saleh
- Department of Biophysics, College of Applied Sciences, University Of Anbar, Anbar, Iraq
| | | | - Farkhod Tursunbaev
- MD, Independent Researcher, "Medcloud" educational centre, Tashkent, Uzbekistan
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
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Budi HS, Younus LA, Lafta MH, Parveen S, Mohammad HJ, Al-qaim ZH, Jawad MA, Parra RMR, Mustafa YF, Alhachami FR, Karampoor S, Mirzaei R. The role of miR-128 in cancer development, prevention, drug resistance, and immunotherapy. Front Oncol 2023; 12:1067974. [PMID: 36793341 PMCID: PMC9923359 DOI: 10.3389/fonc.2022.1067974] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 12/30/2022] [Indexed: 02/03/2023] Open
Abstract
A growing body of evidence has revealed that microRNA (miRNA) expression is dysregulated in cancer, and they can act as either oncogenes or suppressors under certain conditions. Furthermore, some studies have discovered that miRNAs play a role in cancer cell drug resistance by targeting drug-resistance-related genes or influencing genes involved in cell proliferation, cell cycle, and apoptosis. In this regard, the abnormal expression of miRNA-128 (miR-128) has been found in various human malignancies, and its verified target genes are essential in cancer-related processes, including apoptosis, cell propagation, and differentiation. This review will discuss the functions and processes of miR-128 in multiple cancer types. Furthermore, the possible involvement of miR-128 in cancer drug resistance and tumor immunotherapeutic will be addressed.
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Affiliation(s)
- Hendrik Setia Budi
- Department of Oral Biology, Dental Pharmacology, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Laith A. Younus
- Department of Clinical Laboratory Sciences, Faculty of Pharmacy, Jabir Ibn, Hayyan Medical University, Al Najaf Al Ashraf, Iraq
| | | | - Sameena Parveen
- Department of Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, Jazan University, Jazan, Saudi Arabia
| | | | | | | | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
| | - Firas Rahi Alhachami
- Radiology Department, College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Nasiriyah, Iraq
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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Bhattacharyya P, Biswas A, Biswas SC. Brain-enriched miR-128: Reduced in exosomes from Parkinson's patient plasma, improves synaptic integrity, and prevents 6-OHDA mediated neuronal apoptosis. Front Cell Neurosci 2023; 16:1037903. [PMID: 36713778 PMCID: PMC9879011 DOI: 10.3389/fncel.2022.1037903] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 12/29/2022] [Indexed: 01/13/2023] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the death of mid-brain dopaminergic neurons. Unfortunately, no effective cure or diagnostic biomarkers for PD are available yet. To address this, the present study focuses on brain-enriched small non-coding regulatory RNAs called microRNAs (miRNAs) that are released into the circulation packaged inside small extracellular vesicles called exosomes. We collected blood samples from PD patients and isolated exosomes from the plasma. qPCR-based detection revealed a particular neuron-enriched miR-128 to be significantly decreased in the patient-derived exosomes. Interestingly, a concomitant decreased expression of miR-128 was observed in the cellular models of PD. Fluorescent live cell imaging and flow-cytometry revealed that over-expression of miR-128 can prevent 6-OHDA-mediated mitochondrial superoxide production and induction of neuronal death respectively. This neuroprotective effect was found to be induced by miR-128-mediated inhibition of FoxO3a activation, a transcription factor involved in apoptosis. miR-128 over-expression also resulted in down-regulation of pro-apoptotic FoxO3a targets- FasL and PUMA, at both transcript and protein levels. Further downstream, miR-128 over-expression inhibited activation of caspases-8, -9 and -3, preventing both the intrinsic and extrinsic pathways of apoptosis. Additionally, over expression of miR-128 prevented down-regulation of synaptic proteins- Synaptophysin and PSD-95 and attenuated neurite shortening, thereby maintaining overall neuronal integrity. Thus, our study depicts the intracellular role of miR-128 in neuronal apoptosis and neurodegeneration and its implications as a biomarker being detectable in the circulating exosomes of PD patient blood. Thus, characterization of such exosomal brain-enriched miRNAs hold promise for effective detection and diagnosis of PD.
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Affiliation(s)
- Pallabi Bhattacharyya
- Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Atanu Biswas
- Department of Neurology, Bangur Institute of Neurosciences, Kolkata, India
| | - Subhas C. Biswas
- Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India,*Correspondence: Subhas C. Biswas, ;
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Wiltbank AT, Steinson ER, Criswell SJ, Piller M, Kucenas S. Cd59 and inflammation regulate Schwann cell development. eLife 2022; 11:e76640. [PMID: 35748863 PMCID: PMC9232220 DOI: 10.7554/elife.76640] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 06/01/2022] [Indexed: 11/13/2022] Open
Abstract
Efficient neurotransmission is essential for organism survival and is enhanced by myelination. However, the genes that regulate myelin and myelinating glial cell development have not been fully characterized. Data from our lab and others demonstrates that cd59, which encodes for a small GPI-anchored glycoprotein, is highly expressed in developing zebrafish, rodent, and human oligodendrocytes (OLs) and Schwann cells (SCs), and that patients with CD59 dysfunction develop neurological dysfunction during early childhood. Yet, the function of Cd59 in the developing nervous system is currently undefined. In this study, we demonstrate that cd59 is expressed in a subset of developing SCs. Using cd59 mutant zebrafish, we show that developing SCs proliferate excessively and nerves may have reduced myelin volume, altered myelin ultrastructure, and perturbed node of Ranvier assembly. Finally, we demonstrate that complement activity is elevated in cd59 mutants and that inhibiting inflammation restores SC proliferation, myelin volume, and nodes of Ranvier to wildtype levels. Together, this work identifies Cd59 and developmental inflammation as key players in myelinating glial cell development, highlighting the collaboration between glia and the innate immune system to ensure normal neural development.
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Affiliation(s)
- Ashtyn T Wiltbank
- Neuroscience Graduate Program, University of VirginiaCharlottesvilleUnited States
- Program in Fundamental Neuroscience, University of VirginiaCharlottesvilleUnited States
| | - Emma R Steinson
- Department of Biology, University of VirginiaCharlottesvilleUnited States
| | - Stacey J Criswell
- Department of Cell Biology, University of VirginiaCharlottesvilleUnited States
| | - Melanie Piller
- Department of Biology, University of VirginiaCharlottesvilleUnited States
| | - Sarah Kucenas
- Neuroscience Graduate Program, University of VirginiaCharlottesvilleUnited States
- Program in Fundamental Neuroscience, University of VirginiaCharlottesvilleUnited States
- Department of Biology, University of VirginiaCharlottesvilleUnited States
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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7
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Ghosh S, Kumar V, Mukherjee H, Lahiri D, Roy P. Nutraceutical regulation of miRNAs involved in neurodegenerative diseases and brain cancers. Heliyon 2021; 7:e07262. [PMID: 34195404 PMCID: PMC8225984 DOI: 10.1016/j.heliyon.2021.e07262] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 02/24/2021] [Accepted: 06/05/2021] [Indexed: 12/12/2022] Open
Abstract
The human brain is a well-connected, intricate network of neurons and supporting glial cells. Neurodegenerative diseases arise as a consequence of extensive loss of neuronal cells leading to disruption of their natural structure and function. On the contrary, rapid proliferation and growth of glial as well as neuronal cells account for the occurrence of malignancy in brain. In both cases, the molecular microenvironment holds pivotal importance in the progression of the disease. MicroRNAs (miRNA) are one of the major components of the molecular microenvironment. miRNAs are small, noncoding RNAs that control gene expression post-transcriptionally. As compared to other tissues, the brain expresses a substantially high number of miRNAs. In the early stage of neurodegeneration, miRNA expression upregulates, while in oncogenesis, miRNA expression is gradually lost. Neurodegeneration and brain cancer is presumed to be under the influence of identical pathways of cell proliferation, differentiation and cell death which are tightly regulated by miRNAs. It has been confirmed experimentally that miRNA expression can be regulated by nutraceuticals - macronutrients, micronutrients or natural products derived from food; thereby making dietary supplements immensely significant for targeting miRNAs having altered expression patterns during neurodegeneration or oncogenesis. In this review, we will discuss in detail, about the common miRNAs involved in brain cancers and neurodegenerative diseases along with the comprehensive list of miRNAs involved separately in both pathological conditions. We will also discuss the role of nutraceuticals in the regulation of those miRNAs which are involved in both of these pathological conditions.
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Affiliation(s)
- Souvik Ghosh
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247667, India
- Biomaterials and Multiscale Mechanics Laboratory, Department of Metallurgical and Materials Engineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247667, India
- Centre of Nanotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247667, India
| | - Viney Kumar
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247667, India
| | - Haimanti Mukherjee
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247667, India
| | - Debrupa Lahiri
- Biomaterials and Multiscale Mechanics Laboratory, Department of Metallurgical and Materials Engineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247667, India
- Centre of Nanotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247667, India
| | - Partha Roy
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247667, India
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8
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UPF2 leads to degradation of dendritically targeted mRNAs to regulate synaptic plasticity and cognitive function. Mol Psychiatry 2020; 25:3360-3379. [PMID: 31636381 PMCID: PMC7566522 DOI: 10.1038/s41380-019-0547-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 08/13/2019] [Accepted: 08/19/2019] [Indexed: 12/21/2022]
Abstract
Synaptic plasticity requires a tight control of mRNA levels in dendrites. RNA translation and degradation pathways have been recently linked to neurodevelopmental and neuropsychiatric diseases, suggesting a role for RNA regulation in synaptic plasticity and cognition. While the local translation of specific mRNAs has been implicated in synaptic plasticity, the tightly controlled mechanisms that regulate local quantity of specific mRNAs remain poorly understood. Despite being the only RNA regulatory pathway that is associated with multiple mental illnesses, the nonsense-mediated mRNA decay (NMD) pathway presents an unexplored regulatory mechanism for synaptic function and plasticity. Here, we show that neuron-specific disruption of UPF2, an NMD component, in adulthood attenuates learning, memory, spine density, synaptic plasticity (L-LTP), and potentiates perseverative/repetitive behavior in mice. We report that the NMD pathway operates within dendrites to regulate Glutamate Receptor 1 (GLUR1) surface levels. Specifically, UPF2 modulates the internalization of GLUR1 and promotes its local synthesis in dendrites. We identified neuronal Prkag3 mRNA as a mechanistic substrate for NMD that contributes to the UPF2-mediated regulation of GLUR1 by limiting total GLUR1 levels. These data establish that UPF2 regulates synaptic plasticity, cognition, and local protein synthesis in dendrites, providing fundamental insight into the neuron-specific function of NMD within the brain.
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9
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Sehovic E, Spahic L, Smajlovic-Skenderagic L, Pistoljevic N, Dzanko E, Hajdarpasic A. Identification of developmental disorders including autism spectrum disorder using salivary miRNAs in children from Bosnia and Herzegovina. PLoS One 2020; 15:e0232351. [PMID: 32353026 PMCID: PMC7192422 DOI: 10.1371/journal.pone.0232351] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 04/14/2020] [Indexed: 02/06/2023] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by major social, communication and behavioural challenges. The cause of ASD is still unclear and it is assumed that environmental, genetic and epigenetic factors influence the risk of ASD occurrence. MicroRNAs (miRNAs) are short 21-25 nucleotide long RNA molecules which post-transcriptionally regulate gene expression. MiRNAs play an important role in central nervous system development; therefore, dysregulation of miRNAs is connected to changes in behaviour and cognition observed in many disorders including ASD. Based on previously published work, on diagnosing ASD using miRNAs, we hypothesized that miRNAs can be used as biomarkers in children with suspected developmental disorders (DD) including ASD within Bosnian-Herzegovinian (B&H) population. 14 selected miRNAs were tested on saliva of children with suspected developmental disorders including ASD. The method of choice was qRT-PCR as a relatively cheap method available in most diagnostic laboratories in low to mid-income countries (LMIC). Out of 14 analysed miRNAs, 6 were differentially expressed between typically developing children and children with some type of developmental disorder including autism spectrum disorder. Using the most optimal logistic regression, we were able to distinguish between ASD and typically developing (TD) children. We have found 5 miRNAs as potential biomarkers. From those, 3 were differentially expressed within the ASD cohort. All 5 miRNAs had shown good chi-square statistics within the logistic regression performed on all 14 analysed miRNAs. The accuracy of 5-miRNAs model training set was 90.2%, while the validation set had a 90% accuracy. This study has shown that miRNAs may be considered as biomarkers for ASD detection and may be used to identify children with ASD along with standard developmental screening tests. By combining these methods we may be able to reach a reliable and accessible diagnostic model for children with ASD in LMIC such as B&H.
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Affiliation(s)
- Emir Sehovic
- Genetics and Bioengineering, International Burch University, Sarajevo, Bosnia and Herzegovina
| | - Lemana Spahic
- Genetics and Bioengineering, International Burch University, Sarajevo, Bosnia and Herzegovina
| | | | | | - Eldin Dzanko
- Education for All (EDUS), Sarajevo, Bosnia and Herzegovina
| | - Aida Hajdarpasic
- Department of Medical Biology, Sarajevo Medical School, Sarajevo School of Science and Technology, Sarajevo, Bosnia and Herzegovina
- * E-mail:
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The Complex Relationship between HTLV-1 and Nonsense-Mediated mRNA Decay (NMD). Pathogens 2020; 9:pathogens9040287. [PMID: 32326562 PMCID: PMC7238105 DOI: 10.3390/pathogens9040287] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 04/09/2020] [Accepted: 04/12/2020] [Indexed: 02/07/2023] Open
Abstract
Before the establishment of an adaptive immune response, retroviruses can be targeted by several cellular host factors at different stages of the viral replication cycle. This intrinsic immunity relies on a large diversity of antiviral processes. In the case of HTLV-1 infection, these active innate host defense mechanisms are debated. Among these mechanisms, we focused on an RNA decay pathway called nonsense-mediated mRNA decay (NMD), which can target multiple viral RNAs, including HTLV-1 unspliced RNA, as has been recently demonstrated. NMD is a co-translational process that depends on the RNA helicase UPF1 and regulates the expression of multiple types of host mRNAs. RNA sensitivity to NMD depends on mRNA organization and the ribonucleoprotein (mRNP) composition. HTLV-1 has evolved several means to evade the NMD threat, leading to NMD inhibition. In the early steps of infection, NMD inhibition favours the production of HTLV-1 infectious particles, which may contribute to the survival of the fittest clones despite genome instability; however, its direct long-term impact remains to be investigated.
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11
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Dyle MC, Kolakada D, Cortazar MA, Jagannathan S. How to get away with nonsense: Mechanisms and consequences of escape from nonsense-mediated RNA decay. WILEY INTERDISCIPLINARY REVIEWS. RNA 2020; 11:e1560. [PMID: 31359616 PMCID: PMC10685860 DOI: 10.1002/wrna.1560] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/25/2019] [Accepted: 07/04/2019] [Indexed: 11/04/2023]
Abstract
Nonsense-mediated RNA decay (NMD) is an evolutionarily conserved RNA quality control process that serves both as a mechanism to eliminate aberrant transcripts carrying premature stop codons, and to regulate expression of some normal transcripts. For a quality control process, NMD exhibits surprising variability in its efficiency across transcripts, cells, tissues, and individuals in both physiological and pathological contexts. Whether an aberrant RNA is spared or degraded, and by what mechanism, could determine the phenotypic outcome of a disease-causing mutation. Hence, understanding the variability in NMD is not only important for clinical interpretation of genetic variants but also may provide clues to identify novel therapeutic approaches to counter genetic disorders caused by nonsense mutations. Here, we discuss the current knowledge of NMD variability and the mechanisms that allow certain transcripts to escape NMD despite the presence of NMD-inducing features. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA in Disease and Development > RNA in Disease RNA Turnover and Surveillance > Regulation of RNA Stability.
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Affiliation(s)
- Michael C. Dyle
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Divya Kolakada
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Molecular Biology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Michael A. Cortazar
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Sujatha Jagannathan
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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12
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Rodiño-Janeiro BK, Pardo-Camacho C, Santos J, Martínez C. Mucosal RNA and protein expression as the next frontier in IBS: abnormal function despite morphologically intact small intestinal mucosa. Am J Physiol Gastrointest Liver Physiol 2019; 316:G701-G719. [PMID: 30767681 DOI: 10.1152/ajpgi.00186.2018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Irritable bowel syndrome (IBS) is one of the commonest gastrointestinal disorders. Although long-time considered a pure functional disorder, intense research in past years has rendered a very complex and varied array of observations indicating the presence of structural and molecular abnormalities underlying characteristic motor and sensitive changes and clinical manifestations. Analysis of gene and protein expression in the intestinal mucosa has shed light on the molecular mechanisms implicated in IBS physiopathology. This analysis uncovers constitutive and inductive genetic and epigenetic marks in the small and large intestine that highlight the role of epithelial barrier, immune activation, and mucosal processing of foods and toxins and several new molecular pathways in the origin of IBS. The incorporation of innovative high-throughput techniques into IBS research is beginning to provide new insights into highly structured and interconnected molecular mechanisms modulating gene and protein expression at tissue level. Integration and correlation of these molecular mechanisms with clinical and environmental data applying systems biology/medicine and data mining tools emerge as crucial steps that will allow us to get meaningful and more definitive comprehension of IBS-detailed development and show the real mechanisms and causality of the disease and the way to identify more specific diagnostic biomarkers and effective treatments.
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Affiliation(s)
- Bruno Kotska Rodiño-Janeiro
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca , Barcelona , Spain.,Department of Gastroenterology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (Facultat de Medicina) , Barcelona , Spain
| | - Cristina Pardo-Camacho
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca , Barcelona , Spain.,Department of Gastroenterology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (Facultat de Medicina) , Barcelona , Spain
| | - Javier Santos
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca , Barcelona , Spain.,Department of Gastroenterology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (Facultat de Medicina) , Barcelona , Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas , Madrid , Spain
| | - Cristina Martínez
- Laboratory of Neuro-Immuno-Gastroenterology, Digestive System Research Unit, Vall d'Hebron Institut de Recerca , Barcelona , Spain.,Department of Gastroenterology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (Facultat de Medicina) , Barcelona , Spain
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13
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Grassi E, Santoro R, Umbach A, Grosso A, Oliviero S, Neri F, Conti L, Ala U, Provero P, DiCunto F, Merlo GR. Choice of Alternative Polyadenylation Sites, Mediated by the RNA-Binding Protein Elavl3, Plays a Role in Differentiation of Inhibitory Neuronal Progenitors. Front Cell Neurosci 2019; 12:518. [PMID: 30687010 PMCID: PMC6338052 DOI: 10.3389/fncel.2018.00518] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 12/12/2018] [Indexed: 01/09/2023] Open
Abstract
Alternative polyadenylation (APA) is a widespread mechanism involving about half of the expressed genes, resulting in varying lengths of the 3′ untranslated region (3′UTR). Variations in length and sequence of the 3′UTR may underlie changes of post-transcriptional processing, localization, miRNA targeting and stability of mRNAs. During embryonic development a large array of mRNAs exhibit APA, with a prevalence of the longer 3′UTR versions in differentiating cells. Little is known about polyA+ site usage during differentiation of mammalian neural progenitors. Here we exploit a model of adherent neural stem (ANS) cells, which homogeneously and efficiently differentiate into GABAergic neurons. RNAseq data shows a global trend towards lengthening of the 3′UTRs during differentiation. Enriched expression of the longer 3′UTR variants of Pes1 and Gng2 was detected in the mouse brain in areas of cortical and subcortical neuronal differentiation, respectively, by two-probes fluorescent in situ hybridization (FISH). Among the coding genes upregulated during differentiation of ANS cells we found Elavl3, a neural-specific RNA-binding protein homologous to Drosophila Elav. In the insect, Elav regulates polyA+ site choice while interacting with paused Pol-II promoters. We tested the role of Elavl3 in ANS cells, by silencing Elavl3 and observed consistent changes in 3′UTR length and delayed neuronal differentiation. These results indicate that choice of the polyA+ site and lengthening of 3′UTRs is a possible additional mechanism of posttranscriptional RNA modification involved in neuronal differentiation.
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Affiliation(s)
- Elena Grassi
- Department of Molecular Biotechnology, University of Turin, Turin, Italy
| | - Roberto Santoro
- Department of Molecular Biotechnology, University of Turin, Turin, Italy
| | - Alessandro Umbach
- Department of Molecular Biotechnology, University of Turin, Turin, Italy
| | - Anna Grosso
- Department of Neurosciences, University of Turin, Turin, Italy
| | - Salvatore Oliviero
- Italian Institute for Genomic Medicine, Turin, Italy.,Department of Life Science and System Biology, University of Turin, Turin, Italy
| | - Francesco Neri
- Italian Institute for Genomic Medicine, Turin, Italy.,Department of Life Science and System Biology, University of Turin, Turin, Italy
| | - Luciano Conti
- Centre for Integrative Biology-CIBIO, University of Trento, Povo, Italy
| | - Ugo Ala
- Department of Molecular Biotechnology, University of Turin, Turin, Italy
| | - Paolo Provero
- Department of Molecular Biotechnology, University of Turin, Turin, Italy
| | - Ferdinando DiCunto
- Department of Molecular Biotechnology, University of Turin, Turin, Italy.,Department of Neurosciences, University of Turin, Turin, Italy
| | - Giorgio R Merlo
- Department of Molecular Biotechnology, University of Turin, Turin, Italy
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14
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Lennox AL, Mao H, Silver DL. RNA on the brain: emerging layers of post-transcriptional regulation in cerebral cortex development. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY 2017; 7. [PMID: 28837264 DOI: 10.1002/wdev.290] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 07/19/2017] [Accepted: 07/20/2017] [Indexed: 12/11/2022]
Abstract
Embryonic development is a critical period during which neurons of the brain are generated and organized. In the developing cerebral cortex, this requires complex processes of neural progenitor proliferation, neuronal differentiation, and migration. Each step relies upon highly regulated control of gene expression. In particular, RNA splicing, stability, localization, and translation have emerged as key post-transcriptional regulatory nodes of mouse corticogenesis. Trans-regulators of RNA metabolism, including microRNAs (miRs) and RNA-binding proteins (RBPs), orchestrate diverse steps of cortical development. These trans-factors function either individually or cooperatively to influence RNAs, often of similar classes, termed RNA regulons. New technological advances raise the potential for an increasingly sophisticated understanding of post-transcriptional control in the developing neocortex. Many RNA-binding factors are also implicated in neurodevelopmental diseases of the cortex. Therefore, elucidating how RBPs and miRs converge to influence mRNA expression in progenitors and neurons will give valuable insights into mechanisms of cortical development and disease. WIREs Dev Biol 2018, 7:e290. doi: 10.1002/wdev.290 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Regulatory RNA Nervous System Development > Vertebrates: Regional Development Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease.
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Affiliation(s)
- Ashley L Lennox
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA
| | - Hanqian Mao
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.,Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
| | - Debra L Silver
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.,Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.,Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
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15
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Hicks SD, Middleton FA. A Comparative Review of microRNA Expression Patterns in Autism Spectrum Disorder. Front Psychiatry 2016; 7:176. [PMID: 27867363 PMCID: PMC5095455 DOI: 10.3389/fpsyt.2016.00176] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 10/11/2016] [Indexed: 11/13/2022] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a wide spectrum of deficits in social interaction, communication, and behavior. There is a significant genetic component to ASD, yet no single gene variant accounts for >1% of incidence. Posttranscriptional mechanisms such as microRNAs (miRNAs) regulate gene expression without altering the genetic code. They are abundant in the developing brain and are dysregulated in children with ASD. Patterns of miRNA expression are altered in the brain, blood, saliva, and olfactory precursor cells of ASD subjects. The ability of miRNAs to regulate broad molecular pathways in response to environmental stimuli makes them an intriguing player in ASD, a disorder characterized by genetic predisposition with ill-defined environmental triggers. In addition, the availability and extracellular stability of miRNAs make them an ideal candidate for biomarker discovery. Here, we discuss 27 miRNAs with overlap across ASD studies, including 3 miRNAs identified in 3 or more studies (miR-23a, miR-146a, and miR-106b). Together, these 27 miRNAs have 1245 high-confidence mRNA targets, a significant number of which are expressed in the brain. Furthermore, these mRNA targets demonstrate over-representation of autism-related genes with enrichment of neurotrophic signaling molecules. Brain-derived neurotrophic factor, a molecule involved in hippocampal neurogenesis and altered in ASD, is targeted by 6 of the 27 miRNAs of interest. This neurotrophic pathway represents one intriguing mechanism by which perturbations in miRNA signaling might influence central nervous system development in children with ASD.
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Affiliation(s)
- Steven D. Hicks
- Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA
| | - Frank A. Middleton
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA
- Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
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16
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Shahbazi S. Nonsense-mediated mRNA decay among coagulation factor genes. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2016; 19:344-9. [PMID: 27279976 PMCID: PMC4887705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
OBJECTIVES Haemostasis prevents blood loss following vascular injury. It depends on the unique concert of events involving platelets and specific blood proteins, known as coagulation factors. The clotting system requires precise regulation and coordinated reactions to maintain the integrity of the vasculature. Clotting insufficiency mostly occurs due to genetically inherited coagulation factor deficiencies such as hemophilia. MATERIALS AND METHODS A relevant literature search of PubMed was performed using the keywords coagulation factors, Nonsense-mediated mRNA decay and premature translation termination codons. Search limitations included English language and human-based studies. RESULTS Mutations that cause premature translation termination codons probably account for one-third of genetically inherited diseases. Transcripts bearing aberrant termination codons are selectively identified and eliminated by an evolutionarily conserved posttranscriptional pathway known as nonsense-mediated mRNA decay (NMD). There are many pieces of evidence of decay among coagulation factor genes. However, the hemophilia gene (F8) does not seem to be subjected to NMD. Since the F8 gene is located on the X-chromosome, a connection between X-linked traits and mRNA decay could be assumed. CONCLUSION Considering that not all genes go through decay, this review focuses on the basics of the mechanism in coagulation genes. It is interesting to determine whether this translation-coupled surveillance system represents a general rule for the genes encoding components of the same physiological cascade.
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Affiliation(s)
- Shirin Shahbazi
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran,Corresponding author: School of Medical Sciences, Tarbiat Modares University, Al-e-Ahmad and Chamran Cross, Tehran, Iran. Tel: +98-21-82884556; Fax: +98-21-82884555;
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17
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Ching AS, Ahmad-Annuar A. A Perspective on the Role of microRNA-128 Regulation in Mental and Behavioral Disorders. Front Cell Neurosci 2015; 9:465. [PMID: 26696825 PMCID: PMC4677093 DOI: 10.3389/fncel.2015.00465] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 11/16/2015] [Indexed: 12/18/2022] Open
Abstract
MiRNAs are short, non-coding RNA molecules that regulate gene expression post-transcriptionally. Over the past decade, misregulated miRNA pathways have been associated with various diseases such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. In this article, we aim to discuss the role played by miR-128 in neuropsychiatric disorders, and highlight potential target genes from an in silico analysis of predicted miR-128 targets. We also discuss the differences of target gene determination based on a bioinformatics or empirical approach. Using data from TargetScan and published reports, we narrowed the miR-128 target gene list to those that are known to be associated with neuropsychiatric disorders, and found that these genes can be classified into 29 gene clusters and are mostly enriched in cancer and MAPK signaling pathways. We also highlight some recent studies on several of the miR-128 targets which should be investigated further as potential candidate genes for therapeutic interventions.
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Affiliation(s)
- Ai-Sze Ching
- Department of Biomedical Science, Faculty of Medicine, University of Malaya Kuala Lumpur, Malaysia
| | - Azlina Ahmad-Annuar
- Department of Biomedical Science, Faculty of Medicine, University of Malaya Kuala Lumpur, Malaysia
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18
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Nomakuchi TT, Rigo F, Aznarez I, Krainer AR. Antisense oligonucleotide-directed inhibition of nonsense-mediated mRNA decay. Nat Biotechnol 2015; 34:164-6. [PMID: 26655495 PMCID: PMC4744113 DOI: 10.1038/nbt.3427] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 11/09/2015] [Indexed: 12/12/2022]
Abstract
Nonsense-mediated mRNA decay (NMD) is a cellular quality-control mechanism that is thought to exacerbate the phenotype of certain pathogenic nonsense mutations by preventing the expression of semi-functional proteins. NMD also limits the efficacy of read-through compound (RTC)-based therapies. Here, we report a gene-specific method of NMD inhibition using antisense oligonucleotides (ASOs), and combine this approach with an RTC to effectively restore the expression of full-length protein from a nonsense-mutant allele.
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Affiliation(s)
- Tomoki T Nomakuchi
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.,Stony Brook University School of Medicine, Stony Brook, New York, USA
| | - Frank Rigo
- Isis Pharmaceuticals, Carslbad, California, USA
| | - Isabel Aznarez
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
| | - Adrian R Krainer
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
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19
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Shum EY, Espinoza JL, Ramaiah M, Wilkinson MF. Identification of novel post-transcriptional features in olfactory receptor family mRNAs. Nucleic Acids Res 2015; 43:9314-26. [PMID: 25908788 PMCID: PMC4627058 DOI: 10.1093/nar/gkv324] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 03/30/2015] [Indexed: 01/23/2023] Open
Abstract
Olfactory receptor (Olfr) genes comprise the largest gene family in mice. Despite their importance in olfaction, how most Olfr mRNAs are regulated remains unexplored. Using RNA-seq analysis coupled with analysis of pre-existing databases, we found that Olfr mRNAs have several atypical features suggesting that post-transcriptional regulation impacts their expression. First, Olfr mRNAs, as a group, have dramatically higher average AU-content and lower predicted secondary structure than do control mRNAs. Second, Olfr mRNAs have a higher density of AU-rich elements (AREs) in their 3'UTR and upstream open reading frames (uORFs) in their 5 UTR than do control mRNAs. Third, Olfr mRNAs have shorter 3' UTR regions and with fewer predicted miRNA-binding sites. All of these novel properties correlated with higher Olfr expression. We also identified striking differences in the post-transcriptional features of the mRNAs from the two major classes of Olfr genes, a finding consistent with their independent evolutionary origin. Together, our results suggest that the Olfr gene family has encountered unusual selective forces in neural cells that have driven them to acquire unique post-transcriptional regulatory features. In support of this possibility, we found that while Olfr mRNAs are degraded by a deadenylation-dependent mechanism, they are largely protected from this decay in neural lineage cells.
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Affiliation(s)
- Eleen Y Shum
- Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA
| | - Josh L Espinoza
- Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA
| | - Madhuvanthi Ramaiah
- Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA
| | - Miles F Wilkinson
- Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA
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20
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Karam R, Lou CH, Kroeger H, Huang L, Lin JH, Wilkinson MF. The unfolded protein response is shaped by the NMD pathway. EMBO Rep 2015; 16:599-609. [PMID: 25807986 DOI: 10.15252/embr.201439696] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 02/24/2015] [Indexed: 12/15/2022] Open
Abstract
Endoplasmic reticulum (ER) stress induces the unfolded protein response (UPR), an essential adaptive intracellular pathway that relieves the stress. Although the UPR is an evolutionarily conserved and beneficial pathway, its chronic activation contributes to the pathogenesis of a wide variety of human disorders. The fidelity of UPR activation must thus be tightly regulated to prevent inappropriate signaling. The nonsense-mediated RNA decay (NMD) pathway has long been known to function in RNA quality control, rapidly degrading aberrant mRNAs, and has been suggested to regulate subsets of normal mRNAs. Here, we report that the NMD pathway regulates the UPR. NMD increases the threshold for triggering the UPR in vitro and in vivo, thereby preventing UPR activation in response to normally innocuous levels of ER stress. NMD also promotes the timely termination of the UPR. We demonstrate that NMD directly targets the mRNAs encoding several UPR components, including the highly conserved UPR sensor, IRE1α, whose NMD-dependent degradation partly underpins this process. Our work not only sheds light on UPR regulation, but demonstrates the physiological relevance of NMD's ability to regulate normal mRNAs.
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Affiliation(s)
- Rachid Karam
- Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Chih-Hong Lou
- Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Heike Kroeger
- Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Lulu Huang
- Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Jonathan H Lin
- Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Miles F Wilkinson
- Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA Institute of Genomic Medicine, University of California San Diego, La Jolla, CA, USA
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21
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Nonsense-mediated decay in genetic disease: friend or foe? MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2014; 762:52-64. [PMID: 25485595 DOI: 10.1016/j.mrrev.2014.05.001] [Citation(s) in RCA: 160] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 05/02/2014] [Accepted: 05/03/2014] [Indexed: 12/11/2022]
Abstract
Eukaryotic cells utilize various RNA quality control mechanisms to ensure high fidelity of gene expression, thus protecting against the accumulation of nonfunctional RNA and the subsequent production of abnormal peptides. Messenger RNAs (mRNAs) are largely responsible for protein production, and mRNA quality control is particularly important for protecting the cell against the downstream effects of genetic mutations. Nonsense-mediated decay (NMD) is an evolutionarily conserved mRNA quality control system in all eukaryotes that degrades transcripts containing premature termination codons (PTCs). By degrading these aberrant transcripts, NMD acts to prevent the production of truncated proteins that could otherwise harm the cell through various insults, such as dominant negative effects or the ER stress response. Although NMD functions to protect the cell against the deleterious effects of aberrant mRNA, there is a growing body of evidence that mutation-, codon-, gene-, cell-, and tissue-specific differences in NMD efficiency can alter the underlying pathology of genetic disease. In addition, the protective role that NMD plays in genetic disease can undermine current therapeutic strategies aimed at increasing the production of full-length functional protein from genes harboring nonsense mutations. Here, we review the normal function of this RNA surveillance pathway and how it is regulated, provide current evidence for the role that it plays in modulating genetic disease phenotypes, and how NMD can be used as a therapeutic target.
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22
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Yap K, Makeyev EV. Regulation of gene expression in mammalian nervous system through alternative pre-mRNA splicing coupled with RNA quality control mechanisms. Mol Cell Neurosci 2013; 56:420-8. [PMID: 23357783 DOI: 10.1016/j.mcn.2013.01.003] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 01/15/2013] [Accepted: 01/17/2013] [Indexed: 12/12/2022] Open
Abstract
Eukaryotic gene expression is orchestrated on a genome-wide scale through several post-transcriptional mechanisms. Of these, alternative pre-mRNA splicing expands the proteome diversity and modulates mRNA stability through downstream RNA quality control (QC) pathways including nonsense-mediated decay (NMD) of mRNAs containing premature termination codons and nuclear retention and elimination (NRE) of intron-containing transcripts. Although originally identified as mechanisms for eliminating aberrant transcripts, a growing body of evidence suggests that NMD and NRE coupled with deliberate changes in pre-mRNA splicing patterns are also used in a number of biological contexts for deterministic control of gene expression. Here we review recent studies elucidating molecular mechanisms and biological significance of these gene regulation strategies with a specific focus on their roles in nervous system development and physiology. This article is part of a Special Issue entitled 'RNA and splicing regulation in neurodegeneration'.
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Affiliation(s)
- Karen Yap
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
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23
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Palacios IM. Nonsense-mediated mRNA decay: from mechanistic insights to impacts on human health. Brief Funct Genomics 2012; 12:25-36. [PMID: 23148322 DOI: 10.1093/bfgp/els051] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Cells are able to recognize and degrade aberrant transcripts in order to self-protect from potentially toxic proteins. Various pathways detect aberrant RNAs in the cytoplasm and are dependent on translation. One of these pathways is the nonsense-mediated RNA decay (NMD). NMD is a surveillance mechanism that degrades transcripts containing nonsense mutations, preventing the translation of possibly harmful truncated proteins. For example, the degradation of a nonsense harming β-globin allele renders normal phenotypes. On the other hand, regulating NMD is also important in those cases when the produced aberrant protein is better than having no protein, as it has been shown for cystic fibrosis. These findings reflect the important role for NMD in human health. In addition, NMD controls the levels of physiologic transcripts, which defines this pathway as a novel gene expression regulator, with huge impact on homeostasis, cell growth and development. While the mechanistic details of NMD are being gradually understood, the physiological role of this RNA surveillance pathway still remains largely unknown. This is a brief and simplified review on various aspects of NMD, such as the nature of the NMD targets, the mechanism of target degradation and the links between NMD and cell growth, animal development and diseases.
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Affiliation(s)
- Isabel M Palacios
- Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, UK.
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