Neuroinflammation constitutes a fundamental cellular process to signal the loss of brain homeostasis. Glial cells play a central role in orchestrating these neuroinflammation processes in both ...deleterious and beneficial ways. These cellular responses depend on their intercellular interactions with neurons, astrocytes, the blood-brain barrier and infiltrated T-cells in the central nervous system. However, this intercellular crosstalk seems to be activated by specific stimuli for each different neurological scenario. This Review summarizes key studies linking neuroinflammation with certain neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson (PS) and Amyotrophic lateral sclerosis (ALS) and for the development of better therapeutic strategies based on immunomodulation.
Introduction
Evidence about coronavirus disease 2019 (COVID‐19) and pregnancy has rapidly increased since December 2019, making it difficult to make rigorous evidence‐based decisions. The objective ...of this overview of systematic reviews is to conduct a comprehensive analysis of the current evidence on prognosis of COVID‐19 in pregnant women.
Material and methods
We used the Living OVerview of Evidence (L·OVE) platform for COVID‐19, which continually retrieves studies from 46 data sources (including PubMed/MEDLINE, Embase, other electronic databases, clinical trials registries, and preprint repositories, among other sources relevant to COVID‐19), mapping them into PICO (population, intervention, control, and outcomes) questions. The search covered the period from the inception date of each database to 13 September 2020. We included systematic reviews assessing outcomes of pregnant women with COVID‐19 and/or their newborns. Two authors independently screened the titles and s, assessed full texts to select the studies that met the inclusion criteria, extracted data, and appraised the risk of bias of each included systematic review. We measured the overlap of primary studies included among the selected systematic reviews by building a matrix of evidence, calculating the corrected covered area, and assessing the level of overlap for every pair of systematic reviews.
Results
Our search yielded 1132 references. 52 systematic reviews met inclusion criteria and were included in this overview. Only one review had a low risk of bias, three had an unclear risk of bias, and 48 had a high risk of bias. Most of the included reviews were highly overlapped among each other. In the included reviews, rates of maternal death varied from 0% to 11.1%, admission to intensive care from 2.1% to 28.5%, preterm deliveries before 37 weeks from 14.3% to 61.2%, and cesarean delivery from 48.3% to 100%. Regarding neonatal outcomes, neonatal death varied from 0% to 11.7% and the estimated infection status of the newborn varied between 0% and 11.5%.
Conclusions
Only one of 52 systematic reviews had a low risk of bias. Results were heterogeneous and the overlap of primary studies was frequently very high between pairs of systematic reviews. High‐quality evidence syntheses of comparative studies are needed to guide future clinical decisions.
Mutations in the cytosine‐5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post‐transcriptional methylation contributes to the human ...disease is currently unknown. By comparing gene expression data with global cytosine‐5 RNA methylomes in patient fibroblasts and NSun2‐deficient mice, we find that loss of cytosine‐5 RNA methylation increases the angiogenin‐mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5′ tRNA‐derived small RNA fragments. Accumulation of 5′ tRNA fragments in the absence of NSun2 reduces protein translation rates and activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Mechanistically, we demonstrate that angiogenin binds with higher affinity to tRNAs lacking site‐specific NSun2‐mediated methylation and that the presence of 5′ tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2‐deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2‐mediated tRNA methylation contributes to human diseases via stress‐induced RNA cleavage.
Synopsis
This study causally links post‐transcriptional methylation‐controlled tRNA identity and their stability to neurological disorders in human.
NSun2‐mediated tRNA methylation protects from endonucleolytic cleavage into small RNA fragments.
tRNA‐derived small RNA fragments are sufficient and required to induce cellular stress responses.
Loss of cytosine‐5 methylation in tRNAs contributes to neuro‐developmental disease through accumulation of tRNA‐derived small RNA fragments.
This study causally links post‐transcriptional methylation‐controlled tRNA identity and their stability to neurological disorders in human.
Autosomal-recessive loss of the NSUN2 gene has been identified as a causative link to intellectual disability disorders in humans. NSun2 is an RNA methyltransferase modifying cytosine-5 in transfer ...RNAs (tRNAs), yet the identification of cytosine methylation in other RNA species has been hampered by the lack of sensitive and reliable molecular techniques. Here, we describe miCLIP as an additional approach for identifying RNA methylation sites in transcriptomes. miCLIP is a customized version of the individual-nucleotide-resolution crosslinking and immunoprecipitation (iCLIP) method. We confirm site-specific methylation in tRNAs and additional messenger and noncoding RNAs (ncRNAs). Among these, vault ncRNAs contained six NSun2-methylated cytosines, three of which were confirmed by RNA bisulfite sequencing. Using patient cells lacking the NSun2 protein, we further show that loss of cytosine-5 methylation in vault RNAs causes aberrant processing into Argonaute-associated small RNA fragments that can function as microRNAs. Thus, impaired processing of vault ncRNA may contribute to the etiology of NSun2-deficiency human disorders.
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•miCLIP detects NSun2-mediated cytosine-5 methylation in RNA•Vault noncoding RNA is methylated by NSun2•Cytosine-5 in Vault RNA determines its processing into small RNA (svRNA)•svRNAs bind to Argonaute proteins and exhibit microRNA-like functions
Comprehensive analyses of cytosine-5 methylation in the RNA transcriptome have previously been hampered by the lack of sensitive and reliable molecular techniques. In this work, Ule, Frye, and colleagues describe the methylation-iCLIP (miCLIP) method that they used to identify target sites of the RNA methyltransferase, NSun2. Among the targeted noncoding RNAs were vault RNAs, previously associated with resistance to chemotherapy in cancer. They further show how NSun2-mediated methylation of vault ncRNAs influences their processing into small microRNA-like molecules.
Abstract
Epitranscriptome modifications are required for structure and function of RNA and defects in these pathways have been associated with human disease. Here we identify the RNA target for the ...previously uncharacterized 5-methylcytosine (m
5
C) methyltransferase NSun3 and link m
5
C RNA modifications with energy metabolism. Using whole-exome sequencing, we identified loss-of-function mutations in
NSUN3
in a patient presenting with combined mitochondrial respiratory chain complex deficiency. Patient-derived fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of NSun3. We show that NSun3 is required for deposition of m
5
C at the anticodon loop in the mitochondrially encoded transfer RNA methionine (mt-tRNA
Met
). Further, we demonstrate that m
5
C deficiency in mt-tRNA
Met
results in the lack of 5-formylcytosine (f
5
C) at the same tRNA position. Our findings demonstrate that
NSUN3
is necessary for efficient mitochondrial translation and reveal that f
5
C in human mitochondrial RNA is generated by oxidative processing of m
5
C.
PURPOSE OF REVIEWSignificant advances have been made in understanding the functional roles of evolutionarily conserved chemical modifications in RNA. By focusing on cytosine-5 methylation, we will ...highlight the latest insight into the mechanisms how posttranscriptional methylation contributes to cell fate decisions, with implications for cancer development.
RECENT FINDINGSSeveral mutations in RNA-modifying enzymes have been identified to cause complex human diseases, and linked posttranscriptional modifications to fundamental cellular processes. Distinct posttranscriptional modifications are implicated in the regulation of stem cell maintenance and cellular differentiation. The dynamic deposition of a methyl mark into noncoding RNAs modulates the adaptive cellular responses to stress and alterations of methylation levels may lead to cancer.
SUMMARYPosttranscriptional modifications such as cytosine-5 methylation are dynamically regulated and may influence tumour development, maintenance, and progression.
Abstract
RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances have been made in understanding the functional role of ...RNA modifications in regulating coding and non-coding RNA processing and function, which in turn thoroughly shape distinct gene expression programmes. They affect diverse biological processes, and the correct deposition of many of these modifications is required for normal development. Alterations of their deposition are implicated in several diseases, including cancer. In this Review, we focus on the occurrence of N
6
-methyladenosine (m
6
A), 5-methylcytosine (m
5
C) and pseudouridine (Ψ) in coding and non-coding RNAs and describe their physiopathological role in cancer. We will highlight the latest insights into the mechanisms of how these posttranscriptional modifications influence tumour development, maintenance, and progression. Finally, we will summarize the latest advances on the development of small molecule inhibitors that target specific writers or erasers to rewind the epitranscriptome of a cancer cell and their therapeutic potential.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Homeostasis of most adult tissues is maintained by balancing stem cell self-renewal and differentiation, but whether post-transcriptional mechanisms can regulate this process is unknown. Here, we ...identify that an RNA methyltransferase (Misu/Nsun2) is required to balance stem cell self-renewal and differentiation in skin. In the epidermis, this methyltransferase is found in a defined sub-population of hair follicle stem cells poised to undergo lineage commitment, and its depletion results in enhanced quiescence and aberrant stem cell differentiation. Our results reveal that post-transcriptional RNA methylation can play a previously unappreciated role in controlling stem cell fate.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt protein synthesis rates to a dynamically changing microenvironment. However, the ...precise cellular mechanisms linking the extrinsic stimulus to the intrinsic RNA modification pathways remain largely unclear. Here, we identified the cytosine-5 RNA methyltransferase NSUN2 as a sensor for external stress stimuli. Exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Using metabolic profiling, we showed that loss of tRNA methylation captured cells in a distinct catabolic state. Mechanistically, loss of NSUN2 altered the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of protein synthesis. The intracellular accumulation of a specific subset of tRFs correlated with the dynamic repression of global protein synthesis. Finally, NSUN2-driven RNA methylation was functionally required to adapt cell cycle progression to the early stress response. In summary, we revealed that changes in tRNA methylation profiles were sufficient to specify cellular metabolic states and efficiently adapt protein synthesis rates to cell stress.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dubowitz syndrome (DS) is an autosomal recessive disorder characterized by the constellation of mild microcephaly, growth and mental retardation, eczema and peculiar facies. Over 140 cases have been ...reported, but the genetic basis is not understood.
We enrolled a multiplex consanguineous family from the United Arab Emirates with many of the key clinical features of DS as reported in previous series. The family was analyzed by whole exome sequencing. RNA splicing was evaluated with reverse-transcriptase PCR, immunostaining and western blotting was performed with specific antibodies, and site-specific cytosine-5-methylation was studied with bisulfite sequencing.
We identified a homozygous splice mutation in the NSUN2 gene, encoding a conserved RNA methyltransferase. The mutation abolished the canonical splice acceptor site of exon 6, leading to use of a cryptic splice donor within an AluY and subsequent mRNA instability. Patient cells lacked NSUN2 protein and there was resultant loss of site-specific 5-cytosine methylation of the tRNA(Asp GTC) at C47 and C48, known NSUN2 targets.
Our findings establish NSUN2 as the first causal gene with relationship to the DS spectrum phenotype. NSUN2 has been implicated in Myc-induced cell proliferation and mitotic spindle stability, which might help explain the varied clinical presentation in DS that can include chromosomal instability and immunological defects.
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