# Methods to map the m7G tRNA methylome

> **NIH NIH R21** · BOSTON CHILDREN'S HOSPITAL · 2020 · $221,250

## Abstract

Project summary
Transfer RNAs (tRNAs) are subject to numerous posttranscriptional modifications including methylation, which
can control tRNA folding, stability, and function in messenger RNA (mRNA) translation. Despite this growing
awareness, the role of RNA modifications, the so-called ‘epitranscriptome’ in mediating brain functions remains
largely unknown. N7-methylguanosine (m7G) is one of the most prevalent tRNA modifications. Recent studies
have linked mutations in components of the in the METTL1-WDR4 m7G tRNA methyltransferase complex with
a distinct form of microcephalic primordial dwarfism characterized by facial dysmorphism, brain malformation,
and severe encephalopathy with seizures. WDR4, located at human chromosome 21q22.3 is also a candidate
gene for some of the Down syndrome phenotypes including mental retardation caused by trisomy of this
chromosomal region in human patients. Indeed, Wdr4 is one a handful of candidate genes whose
overexpression in mouse influences learning and memory in a model of Down syndrome. Interestingly,
monosomy of the same cluster of genes also influences cognition and hippocampal plasticity, supporting that
the precise dosage of certain gene(s) within this chromosomal region is critical for normal brain function. The
primary goal of this exploratory proposal is to develop methods to map m7G modification of tRNAs at single
nucleotide resolution in mouse embryonic stem cells (mESCs), differentiated neurons, and in the adult mouse
brain. The molecular and cellular role of METTL1-WDR4 in m7G modification, translation, and neuronal
differentiation will also be investigated using a mouse embryonic stem cell model. Finally, the effects of altered
WDR4 dosage on m7G tRNA modification, mRNA translation, and neuronal differentiation will be tested using
Down syndrome patient-derived induced pluripotent stem cells (iPSCs). Successful completion of this work will
provide essential tools and technologies to investigate the role of tRNA methylation in disorders of the brain.

## Key facts

- **NIH application ID:** 9824587
- **Project number:** 5R21MH118594-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Richard I. Gregory
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $221,250
- **Award type:** 5
- **Project period:** 2018-12-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9824587

## Citation

> US National Institutes of Health, RePORTER application 9824587, Methods to map the m7G tRNA methylome (5R21MH118594-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9824587. Licensed CC0.

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