RNA modifications modulate gene expression during development

Frye, Michaela; Harada, Bryan T.; Behm, Mikaela; He, Chuan

doi:10.1126/science.aau1646

Cited by 862 publications

(927 citation statements)

References 68 publications

Supporting

Mentioning

857

Contrasting

Unclassified

Order By: Relevance

“…The posttranscriptional modification of transfer RNA (tRNA) has emerged as a critical modulator of biological processes ranging from gene expression to development (Frye, Harada, Behm, & He, 2018; Ranjan & Leidel, 2019). There are over 100 types of tRNA modifications that range from simple methylation to complex modifications involving multiple chemical groups (El Yacoubi, Bailly, & de Crecy‐Lagard, 2012; Ontiveros, Stoute, & Liu, 2019).…”

mentioning

confidence: 99%

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

et al. 2020

View full text Add to dashboard Cite

The human TRMT1 gene encodes an RNA methyltransferase enzyme responsible for catalyzing dimethylguanosine (m2,2G) formation in transfer RNAs (tRNAs). Frameshift mutations in TRMT1 have been shown to cause autosomal-recessive intellectual disability (ID) in the human population but additional TRMT1 variants remain to be characterized. Here, we describe a homozygous TRMT1 missense variant in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes an arginine residue to a cysteine (R323C) within the methyltransferase domain and is expected to perturb protein folding. Patient cells expressing TRMT1-R323C exhibit a deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss of function. Notably, the TRMT1 R323C mutant retains tRNA binding but is unable to rescue m2,2G formation in TRMT1-deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that perturbs tRNA modification activity and demonstrate that m2,2G modifications are disrupted in the cells of patients with TRMT1-associated ID disorders.

show abstract

mentioning

confidence: 99%

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The simplicity of this code has profound implications. Based on work performed in diverse model organism ranging from plants (Arribas-Hernández et al, 2018;Wei et al, 2018) , through insects (Haussmann et al, 2016;Lence et al, 2016) to mammalian systems, m6A at different sites is thought to be recognized by diverse readers that lead to differential outcomes, with some readers leading to increased decay, others impacting translation, others impacting export from the nucleus, and additional readers are still awaiting characterization (Dominissini et al, 2012;Edupuganti et al, 2017;Frye et al, 2018;Fu et al, 2014;Gilbert et al, 2016;Meyer and Jaffrey, 2017;Wang et al, 2014;Zhao et al, 2018) . In addition, diverse erasers are suggested to be at play, also potentially modulating m6A levels (Jia et al, 2011;Mauer et al, 2016;Zheng et al, 2013) .…”

Section: Discussionmentioning

confidence: 99%

Deciphering the ‘m⁶A code’ via quantitative profiling of m⁶A at single-nucleotide resolution

Edelheit

Toth

et al. 2019

Preprint

View full text Add to dashboard Cite

N6-methyladenosine (m 6 A) is the most abundant modification on mRNA, and is implicated in critical roles in development, physiology and disease. The ability to map m 6 A using immunoprecipitation-based approaches has played a critical role in dissecting m 6 A functions and mechanisms of action. Yet, these approaches are of limited specificity, unknown sensitivity, and unable to quantify m6A stoichiometry. These limitations have severely hampered our ability to unravel the factors determining where m6A will be deposited, to which levels (the 'm6A code'), and to quantitatively profile m6A dynamics across biological systems. Here, we used the RNase MazF, which cleaves specifically at unmethylated RNA sites, to develop MASTER-seq for systematic quantitative profiling of m6A sites at 16-25% of all m6A sites at single nucleotide resolution. We established MASTER-seq for orthogonal validation and de novo detection of m6A sites, and for tracking of m6A dynamics in yeast gametogenesis and in early mammalian differentiation. We discover that antibody-based approaches severely underestimate the number of m6A sites, and that both the presence of m6A and its stoichiometry are 'hard-coded' via a simple and predictable code within the extended sequence composition at the methylation sites. This code accounts for~50% of the variability in methylation levels across sites, allows excellent de novo prediction of methylation sites, and predicts methylation acquisition and loss across evolution. We anticipate that MASTER-seq will pave the path towards a more quantitative investigation of m6A biogenesis and regulation in a wide variety of systems, including diverse cell types, stimuli, subcellular components, and disease states.

show abstract

“…RNA modifications are also important for biological processes including development and cancer [9,10]. Noncoding RNA, such as ribosomal RNA and transfer RNA, harbor several types of RNA modifications, and these modifications are indispensable for their proper function [11].…”

Section: Dna and Rna Modificationsmentioning

confidence: 99%

Recent advances in the detection of base modifications using the Nanopore sequencer

Seki

2019

J Hum Genet

112

View full text Add to dashboard Cite

DNA and RNA modifications have important functions, including the regulation of gene expression. Existing methods based on short-read sequencing for the detection of modifications show difficulty in determining the modification patterns of single chromosomes or an entire transcript sequence. Furthermore, the kinds of modifications for which detection methods are available are very limited. The Nanopore sequencer is a single-molecule, long-read sequencer that can directly sequence RNA as well as DNA. Moreover, the Nanopore sequencer detects modifications on long DNA and RNA molecules. In this review, we mainly focus on base modification detection in the DNA and RNA of mammals using the Nanopore sequencer. We summarize current studies of modifications using the Nanopore sequencer, detection tools using statistical tests or machine learning, and applications of this technology, such as analyses of open chromatin, DNA replication, and RNA metabolism.

show abstract

RNA modifications modulate gene expression during development

Cited by 862 publications

References 68 publications

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

Deciphering the ‘m⁶A code’ via quantitative profiling of m⁶A at single-nucleotide resolution

Recent advances in the detection of base modifications using the Nanopore sequencer

Contact Info

Product

Resources

About

RNA modifications modulate gene expression during development

Cited by 862 publications

References 68 publications

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

Deciphering the ‘m6A code’ via quantitative profiling of m6A at single-nucleotide resolution

Recent advances in the detection of base modifications using the Nanopore sequencer

Contact Info

Product

Resources

About

Deciphering the ‘m⁶A code’ via quantitative profiling of m⁶A at single-nucleotide resolution