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Small RNA Modification Sequencing

NM-Seq — Single-Nucleotide tRNA 2'-O-Me Modification Seq

NM-seq resolves 2'-O-methylation (Nm) on tRNA through periodate chemistry: repeated oxidation–elimination–dephosphorylation cycles strip unmodified nucleotides while Nm positions survive, so each protected site is read at single-base precision.

Periodate chemistry · base-resolution Nm · antibody-free

Overview

Base-resolution mapping of 2'-O-methylation across tRNA

2'-O-methylation sits on the ribose 2'-hydroxyl rather than on a base, and it is placed by 2'-O-methyltransferases or by C/D-box snoRNPs. On tRNA the mark shapes the folded architecture and influences decoding, so which positions carry Nm matters as much as whether Nm is present at all.

Arraystar Single-Nucleotide tRNA 2'-O-Me Modification Seq(NM-seq) carries the whole chain: RNA quality control, OED enrichment of methylated fragments, library construction, sequencing and tRNA-aware bioinformatics. Every reported position is placed inside a mature tRNA transcript with its relative coordinate, host tRNA gene, anticodon and isotype, and structural domain.

What is tRNA NM-seq?

NM-seq is an antibody-free chemical sequencing method for 2'-O-methylation on tRNA. Periodate-driven oxidation, elimination and dephosphorylation degrade unmodified nucleotides while 2'-O-methylated positions resist cleavage, so sequencing the surviving fragments maps each Nm site at single-base precision.

Service at a Glance

Standard tRNA 2'-O-methylation project — custom designs and add-on analyses available on request

Service NamePrice
Single-Nucleotide tRNA 2'-O-Me Modification Seq(NM-seq)

Benefits

What Arraystar tRNA NM-seq gives you

Chemical protection, not signal averaging

Each 2'-O-methylated position is fixed to a single nucleotide because the readout depends on chemical resistance rather than on enrichment breadth.

Mature-tRNA coordinates

Sites are reported with relative positions inside mature tRNA transcripts, host tRNA gene attribution, anticodon, isotype and structural-domain context.

No antibody in the tube

Periodate chemistry removes the pull-down bias and cross-reactivity that antibody capture brings to compact, structured tRNA.

Repeated-cycle enrichment

Iterative OED rounds concentrate methylated fragments so that lower-abundance Nm positions remain visible.

Isotype-level comparison

Positions can be compared across tRNA isotypes and isoacceptors within a single experiment.

One service, sample to data

RNA QC, tRNA processing, library preparation, sequencing and bioinformatics are delivered as a single project.

Background

Why Nm on tRNA needs a chemistry-first readout

Nm modifies the 2'-hydroxyl of the ribose instead of the base, which leaves it invisible to base-modification assays and calls for a chemistry-sensitive approach. The mark is deposited by 2'-O-methyltransferases and by C/D-box snoRNPs, and in tRNA it reinforces the folded L-shaped architecture while tuning decoding (2).

Periodate reacts with the free 2'-hydroxyl of unmodified nucleotides and leaves 2'-O-methylated positions untouched. Cycling oxidation, elimination and dephosphorylation therefore erases the unmodified background and leaves Nm-bearing fragments to be sequenced; Arraystar applies this chemistry in a tRNA setting so that protection is scored inside mature transcripts (1).

tRNA 2'-O-methylation
Figure 1. NM-seq scheme. Periodate-based OED cycles remove unmodified nucleotides while 2'-O-methylated positions survive, so the surviving fragments mark each Nm site.

tRNA 2'-O-Me NM-Seq Workflow

From total RNA to a base-resolution Nm map

Four handling stages carry the sample to a base-resolution Nm dataset: RNA QC and tRNA processing, repeated OED enrichment of methylated fragments, adapter ligation and sequencing, then tRNA-aware alignment and site calling.

tRNA 2'-O-Me NM-Seq Workflow
Figure 2. Single-Nucleotide tRNA 2'-O-Me Modification Seq workflow.

Bioinformatics & Deliverables

Bioinformatics for NM-seq

Reads are aligned against a curated tRNA reference and the positions that escaped OED degradation are called as Nm sites. Reporting covers per-position stoichiometry, motif context, differential modification between groups and browser-ready signal tracks.

Standard Deliverables

Research Applications

Where tRNA Nm profiling fits

tRNA folding and stability

Relates 2'-O-methylated positions to the folded L-shaped architecture and to tRNA turnover.

Decoding and wobble chemistry

Places Nm inside anticodon and wobble context to test its effect on decoding.

Isotype-resolved profiling

Compares Nm occupancy between tRNA isotypes and isoacceptors in the same run.

Disease and biomarker screens

Finds differentially 2'-O-methylated tRNA positions between conditions.

Cross-modification studies

Sits alongside other single-base tRNA assays when a modification landscape is being assembled.

Sample Requirements

Sample handling and submission for tRNA 2'-O-methylation

Sample Storage

  • For cells/tissue: use TRIzol or an RNA-stabilizing reagent, quick-freeze in liquid nitrogen, and keep at –80 °C.
  • For RNA: dissolve in ethanol or RNase-free water, store at –80 °C, and limit freeze–thaw cycles.

Shipping Instructions

  • Transfer each sample into a 1.5 mL nuclease-free tube.
  • Close the tube securely with parafilm or a cap lock to preserve integrity.
  • Send on dry ice with sufficient insulation to sustain the required temperature.
Sample TypeNotes
Whole bloodUse EDTA tubes only; heparin is not compatible with subsequent analytical procedures.
Cultured cellsCell pellets are preferred to ensure high-quality material for processing.
TissueProvide fresh or frozen specimens and avoid necrotic material.
Total RNAMaintain an OD 260/280 ratio ≥ 1.8 and RIN ≥ 7 with no visible degradation. Submit at least 100–300 µg total RNA.

Submit at least 100–300 µg total RNA per sample; the higher end covers samples with lower tRNA content. Questions: support@arraystar.com

FAQ

Questions we are asked about tRNA NM-seq

How does NM-seq pin an Nm site to one nucleotide?
Periodate attacks the free 2'-hydroxyl of unmodified nucleotides, and repeated oxidation, elimination and dephosphorylation cycles remove them. A 2'-O-methylated position blocks that reaction, so the boundary of the surviving fragment marks the modified nucleotide itself rather than indicating a broadly modified region.
Why is antibody-based capture a poor fit for tRNA?
Antibody methods depend on enrichment and resolve regions rather than single positions, and dense tRNA folding limits access to compact transcripts. NM-seq reads chemical protection directly, so it avoids pull-down bias and reports quantitative site-level rather than region-level signal at every 2'-O-methylated position detected in the sample.
Which tRNA features come with each site?
Each reported position is placed inside a mature tRNA transcript with its relative coordinate, the host tRNA gene, the anticodon, the isotype and the structural domain. That context is what lets a site be tied to a specific tRNA rather than to a coordinate alone.
How much total RNA does the assay need?
We ask for 100–300 µg of total RNA per sample, with the higher end recommended when tRNA content is low. Material should show an OD 260/280 ratio of 1.8 or higher and no visible degradation at the QC step. Please contact support before submitting smaller amounts.
Can NM-seq be compared across isotypes?
Yes. Because every site is annotated with its host gene, anticodon and isotype, positions can be compared between isotypes and isoacceptors. Differential modification can also be tested between sample groups within the same reference framework, so comparisons stay consistent across the whole project.
What is the difference between NM-seq and a base-modification assay?
Base-modification assays such as bisulfite or mutation-signature methods read chemical changes at the nucleobase. Nm leaves the base untouched, so NM-seq instead detects resistance of the ribose 2'-hydroxyl, which is why it needs periodate chemistry and a separate OED enrichment step.

Selected Publications

Key references for tRNA 2'-O-methylation

  1. Dai Q, Moshitch-Moshkovitz S, Han D, et al. Nm-seq maps 2'-O-methylation sites in human mRNA with base precision. Nature Methods, 2017. PMID: 28504680
  2. Ringeard M, Marchand V, Decroly E, et al. FTSJ3 is an RNA 2'-O-methyltransferase recruited by HIV to avoid innate immune sensing. Nature, 2019. PMID: 30626973

Map 2'-O-methylation Across Your tRNA Samples

Arraystar tRNA NM-seq pairs periodate chemistry with mature-tRNA annotation — send us the sample set and we will return a base-resolution Nm map with per-site stoichiometry.