N1-methyladenosine modification in mitochondrial tRNAs is associated with Alzheimer’s disease
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ABSTRACT:
PROVIDER: PRJNA706440 | ENA |
REPOSITORIES: ENA
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2018-10-29 | GSE106601 | GEO
Project description:N1-Methyladenosine (m1A) is a prevalent post-transcriptional RNA modification, yet little is known about its abundance, topol- ogy and dynamics in mRNA. Here, we show that m1A is prevalent in Homo sapiens mRNA, which shows an m1A/A ratio of ~0.02%. We develop the m1A-ID-seq technique, based on m1A immunoprecipitation and the inherent ability of m1A to stall reverse tran- scription, as a means for transcriptome-wide m1A profiling. m1A-ID-seq identifies 901 m1A peaks (from 600 genes) in mRNA and noncoding RNA and reveals a prominent feature, enrichment in the 5' untranslated region of mRNA transcripts, that is dis- tinct from the pattern for N6-methyladenosine, the most abundant internal mammalian mRNA modification. Moreover, m1A in mRNA is reversible by ALKBH3, a known DNA/RNA demethylase. Lastly, we show that m1A methylation responds dynamically to stimuli, and we identify hundreds of stress-induced m1A sites. Collectively, our approaches allow comprehensive analysis of m1A modification and provide tools for functional studies of potential epigenetic regulation via the reversible and dynamic m1A methylation.
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Project description:To investigate the function of N1-methyladenosine methylome (m1A) in ocular melanoma, we analyzed m1A enrichment level in ocular melanoma and melanocyte cell lines and established ALKBH3 knock down cell lines in 92.1.
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Project description:Eukaryotic transfer RNAs (tRNA) contain on average 13 modifications that perform a wide range of roles in translation and in the generation of tRNA fragments that regulate gene expression. Queuosine (Q) modification occurs in the wobble anticodon position of tRNAs for amino acids His, Asn, Tyr, and Asp. In eukaryotes, Q modification is fully dependent on diet or on gut microbiome in multi-cellular organisms. Despite decades of study, cellular roles of Q modification remain to be fully elucidated. Here we show that in human cells, Q modification specifically protects its cognate tRNAHis and tRNAAsn against cleavage by ribonucleases. We generated cell lines that contain completely depleted or fully Q-modified tRNAs. Using these resources, we found that Q modification significantly reduces angiogenin cleavage of its cognate tRNAs in vitro. Q modification does not change the cellular abundance of the cognate full-length tRNAs, but alters the cellular content of their fragments in vivo in the absence and presence of stress. Our results provide a new biological aspect of Q modification and a mechanism of how Q modification alters small RNA pool in human cells.
2018-08-10 | GSE102570 | GEO
Project description:Chemical modifications on mRNA are increasingly recognized as a critical regulatory layer of the flow of genetic information, but quantitative tools to monitor RNA modifications in a whole-transcriptome and site-specific manner are lacking. Here we describe a versatile directed evolution platform that rapidly selects for reverse transcriptases that install mutations during reverse transcription at sites of a given type of RNA modification, allowing for site-specific identification of the modification. To develop and validate the platform, we evolved the HIV-1 reverse transcriptase against N1-methyladenosine (m1A). Iterative rounds of selection yielded reverse transcriptases with both robust read-through and high mutation rates at m1A sites. We apply the evolved reverse transcriptase to identify thousands of statistically confident m1A sites in human mRNA, some of which can be detected in antibody-free RNA-seq libraries. Together, this work develops and validates the reverse transcriptase evolution platform and provides new tools, analysis methods, and datasets to study m1A biology.
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Project description:N1-methyladenosine methylome in messenger RNA in petunia
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Project description:N6-Methyladenosine Modification Controls Circular RNA Immunity.
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Project description:N1-methyladenosine is a unique base methylation because it blocks Watson-Crick base paring and introduces a positive charge. Previous studies showed that m1A is prevalent in yeast and mammals mRNA and has a functional role in promoting translation of methylated mRNA. However, little is known about its abundance, topology and dynamics in plant mRNA. In this study, dot blotting and LC–MS/MS analyses reveal a dynamic pattern of m1A mRNA modification in various tissues and at different developmental stages in petunia (Petunia hybrida). Transcriptome-wide profiling of mRNA m1A in petunia was reported by applying m1A mRNA immunoprecipitation followed by a deep-sequencing approach (m1A-seq). m1A-seq analysis identified 4993 m1A peaks in 3231 expressed genes in petunia corollas. Each methylated gene averagely carries 1.55 peaks. Among the identified m1A peaks, there are 251 m1A peaks in which the adenines was partly replaced by thymine (T) and/or the reverse transcription stops happened in adenine site, in 199 expressed genes. We found that m1A is enriched in coding sequences with one peaks located immediately after start codons, and a slight negative correlation between methylated genes and gene expression was observed. Totally, ethylene treatment reduced the m1A level of mRNA in petunia corollas. We show that a RNA m1A-methyltransferase, tRNA specific methyltransferase 61A (PhTRMT61A), is an m1A mRNA methyltransferase. PhTRMT61A silencing results in decreased m1A peaks in mRNA in leaves and abnormal leaf development. PhTRMT61A is located to the nucleus. Our results suggest that m1A in mRNA is an important epitranscriptome marker and plays a role in plant development.
2020-08-12 | GSE136921 | GEO
Project description:A subset of eukaryotic tRNAs is methylated in the anticodon loop to form the 3-methylcytosine (m3C) modification. In mammals, the number of tRNAs containing m3C has expanded to include mitochondrial (mt) tRNA-Ser-UGA and mt-tRNA-Thr-UGU. Whereas the enzymes catalyzing m3C formation in nuclear-encoded cytoplasmic tRNAs have been identified, the proteins responsible for m3C modification in mt-tRNAs are unknown. Here, we show that m3C formation in human mt-tRNAs is dependent upon the Methyltransferase-Like 8 (METTL8) enzyme. We find that METTL8 is a mitochondria-associated protein that interacts with mitochondrial seryl-tRNA synthetase along with mt-tRNAs containing m3C. Human cells deficient in METTL8 exhibit loss of m3C modification in mt-tRNAs but not nuclear-encoded tRNAs. Consistent with the mitochondrial import of METTL8, the formation of m3C in METTL8-deficient cells can be rescued by re-expression of wildtype METTL8 but not by a METTL8 variant lacking the N-terminal mitochondrial localization signal. Notably, METTL8-deficiency in human cells causes alterations in the native migration pattern of mt-tRNA-Ser-UGA suggesting a role for m3C in tRNA folding. Altogether, these findings demonstrate that METTL8 is required for m3C formation in mitochondrial tRNAs and uncover a potential role for m3C modification in mitochondrial tRNA structure.
2022-05-19 | PXD030418 | Pride