# Sperm tsRNAs and their RNA modifications in diet-induced epigenetic inheritance

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2020 · $293,215

## Abstract

Project Summary
Increasing lines of evidence in mammals have shown that certain acquired traits during paternal environmental
exposure could be “memorized” in sperm and transmitted to the future generations, implicating epigenetic
inheritance via the sperm. Particularly, diet-induced metabolic disorders in the father are heritable in mammals,
suggesting this type of epigenetic inheritance has a long-term impact in many metabolic-related human diseases.
To date, the exact sperm “epigenetic carrier” that responds to paternal dietary changes and transmits the
intergenerational phenotype has remained elusive, but presumably involves DNA methylation, chromatin status or
non-coding RNAs. Recently, in a high-fat diet (HFD) mouse model, we showed that highly enriched, tRNA-derived
small RNAs (tsRNAs) from sperm are altered in both expression profiles and RNA modification after paternal HFD
exposure. We also showed that sperm tsRNAs, along with their RNA modifications, are required for
intergenerational transmission of paternally acquired metabolic disorders (Chen et.al. Science, 2016). This
discovery raises the open question of how sperm tsRNAs, along with their RNA modifications, mediate the
embryonic developmental programming that affects the offspring phenotype (Chen et.al. Nat Rev Genet, 2016). To
understand the underlying mechanisms, we propose to (1) identify the target of sperm tsRNAs by injecting sperm
tsRNAs (from HFD and control males) into zygotes, followed by comparative single-cell embryo RNA-seq of 2- to
4-cell embryos and bioinformatics analysis. (2) Because significant alterations of m5C (5-methylcytidine) in sperm
tsRNAs from HFD males have been found, we will determine whether the m5C cytosine RNA methyltransferase,
DNMT2, is essential for sperm tsRNAs to transmit acquired metabolic disorder to offspring, by utilizing HFD model
in Dnmt2-/- and Dnmt2+/+ male mice, and injecting their sperm tsRNAs into normal zygote followed by examining
the metabolic phenotype of F1 offspring. (3) Moreover, in the Dnmt2-/- versus Dnmt2+/+ HFD model, we will
examine the changes of RNA expression profiles by RNA-seq, and the RNA modification profiles in sperm tsRNAs
by a high-throughput approach (based on Liquid chromatography-tandem mass spectrometry, LC-MS/MS) to
quantify multiple RNA modifications, which not only will detect the changes of m5C, but also discover novel RNA
modification changes in the presence or absence of DNMT2. Data from the proposed study will provide insights
into the mechanism by which sperm tsRNAs mediate intergenerational inheritance of acquired metabolic disorders
and facilitate our understanding of the etiology of human diseases originated from diet-based transgenerational
effect.

## Key facts

- **NIH application ID:** 9989145
- **Project number:** 5R01HD092431-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Qi Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $293,215
- **Award type:** 5
- **Project period:** 2017-08-09 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989145

## Citation

> US National Institutes of Health, RePORTER application 9989145, Sperm tsRNAs and their RNA modifications in diet-induced epigenetic inheritance (5R01HD092431-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989145. Licensed CC0.

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