# Mechanism Underlying the Transduction of Epimutations from the Soma to the Male Germline

> **NIH NIH P50** · LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER · 2022 · $265,263

## Abstract

Project Summary 
Most of the studies on epigenetic inheritance focus on the identification of sperm-borne factors that carry 
the epigenetic memory and how they act on the epigenome/genome of the embryos so that the specific 
epigenetic memory can be recalled and manifested as a specific phenotype in offspring. However, one 
fundamental question remains unanswered: given that the effects of exposures, either environmental or 
dietary, are presumably initially manifested as epigenetic changes in directly exposed somatic cells (e.g. 
pancreatic islet cells, adipocytes, hepatocytes, etc.), how do the phenotype-specific epimutations in 
somatic cells get transduced into spermatozoa? Using a highly reproducible mouse model for 
intergenerational epigenetic inheritance of a high fat diet (HFD)-induced metabolic disorders, we here 
propose a series of experiments to tackle this critical question. Our central hypothesis is that HFD- 
induced epimutations in somatic cells can lead to production of specific sncRNAs that are either 
encapsulated in extracellular vesicles (EVs), or present as mobile RNAs, which act as the carrier of 
epigenetic memory once internalized by spermatozoa through either 1) the intra-testicular mechanism 
(i.e., Sertoli cell HDF-specific epigenetic information transmitted to all developing male germ cells or 
directly to spermatozoa during spermatogenesis in the testis), or 2) the post-testicular pathway (i.e., 
HFD-specific epigenetic information transmitted from male reproductive tract epithelial cells to 
spermatozoa), or 3) a combination of both. To test our hypothesis, we propose to identify when and 
where male germ cells gain the ability to transmit the HDF-induced metabolic disorder phenotype (Aim1), 
to study how the intra-testicular pathway contributes to the HFD-specific sperm epigenome (Aim2), to 
study how the post-testicular pathway influences HFD-specific sperm epigenome (Aim3). Data to be 
obtained will help fill the knowledge gap in our understanding of the molecular mechanisms underlying 
the intergenerational epigenetic inheritance of paternally acquired traits in general.

## Key facts

- **NIH application ID:** 10260435
- **Project number:** 5P50HD098593-03
- **Recipient organization:** LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
- **Principal Investigator:** Wei Yan
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $265,263
- **Award type:** 5
- **Project period:** 2019-09-13 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10260435

## Citation

> US National Institutes of Health, RePORTER application 10260435, Mechanism Underlying the Transduction of Epimutations from the Soma to the Male Germline (5P50HD098593-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10260435. Licensed CC0.

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