# Germline Utx mutation as a model for transgenerational epigenetic inheritance

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $390,652

## Abstract

PROJECT SUMMARY
Male gametes transmit the paternal genome to the next generation. At the same time, they also carry
epigenetic information that is passed to the zygote at fertilization. A major unanswered question is whether this
inherited epigenetic information influences gene expression, phenotype, and disease susceptibility in offspring.
We have found that knocking out the chromatin regulator gene Utx in the mouse male germ line leads to
reduced survival and increased rates of tumor formation in offspring, even when offspring do not themselves
carry a Utx mutation. This proposal will test the hypothesis that loss of Utx in male germ cells induces
epigenetic changes in the gametes that alter gene expression after fertilization and ultimately result in the
increased tumor susceptibility observed in offspring. Specifically, the experiments proposed here will examine
genome-wide changes in histone modification, DNA methylation, and gene expression in developing and
mature male gametes of Utx conditional knockouts (Aim 1); evaluate gene expression and phenotypic effects
in embryos of the next generation at the preimplantation and perinatal stages (Aim 2); and define changes in
histone modification, DNA methylation, and gene expression in developing and mature germ cells of offspring
in order to determine if these changes can persist across multiple generations (Aim 3).
The ultimate goal of this study is to understand how changes in the development and gene regulatory state of
mammalian male germ cells can impact phenotype and disease in progeny. In the past, this question has
been addressed primarily by manipulating the paternal environment using chemical or nutritional exposures,
which are difficult to control precisely. In contrast, this study will employ a simple, well-defined and highly
reproducible genetic manipulation that can be used to generate germline epigenetic changes. The proposed
experiments will elucidate a new mechanism by which epigenetic misregulation in male gametes can contribute
to male infertility, a priority area for NICHD. The results will also frame a new mechanism for non-genetic
inheritance of disease susceptibility, with broad implications for the etiology and epidemiology of common
diseases such as cancer and diabetes.

## Key facts

- **NIH application ID:** 10149366
- **Project number:** 5R01HD098128-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Bluma J Lesch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,652
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149366

## Citation

> US National Institutes of Health, RePORTER application 10149366, Germline Utx mutation as a model for transgenerational epigenetic inheritance (5R01HD098128-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10149366. Licensed CC0.

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