# Mechanisms of transgenerational epigenetic inheritance

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $347,317

## Abstract

Project Summary/Abstract
Environmental factors increase the frequency of metabolic disorders. The mechanisms by which
these epiphenotypes are transmitted between the exposed and subsequent generations through
the paternal germline remains poorly understood. The nuclei of mammalian sperm are highly
condensed, the DNA is mostly covered by protamines with only a few retained nucleosomes,
and epigenetic information stored in the form of DNA methylation is quickly erased from paternal
chromosomes shortly after fertilization. Experiments carried out in our lab suggest a more
complex picture of mouse sperm, suggesting the presence of multiple histone modifications,
nucleosomes positioned around transcription start sites and transcription factor binding sites,
presence of CTCF, cohesin, condensin, FoxA1, Oct4, Nanog, Mediator and RNAPII
phosphorylated in Ser2. We also find thousands of enhancers and super-enhancers in a poised
or active epigenetic state based on the presence of both specific histone modifications and
transcription factors. This information suggests that mammalian sperm contain a rich and
complex palette of epigenetic information that could be altered by environmental factors to paint
novel phenotypic outcomes in the next generation. In this application, we propose to carry out
experiments to dissect the mechanisms by which epigenetic information is established and
altered by the environment during male germline development, how this information is stored in
sperm, and how it is transmitted to the somatic cells of adult tissues of the next generation. To
accomplish this we will use obese mice who are 4th generation descendants of females exposed
to Bisphenol A (BPA) during pregnancy. We will use mass spectrometry to identify a wide range
of transcription factors present in sperm, and ChIP-seq to examine differences in the distribution
of these transcription factors in the sperm of control versus obese mice. We will then use
Chromosome Conformation Capture techniques to examine the consequence of alterations in
transcription factor binding on the 3D architecture of mouse sperm. To understand how and
when differences in the epigenome of control and obese mice are established, we will examine
the effect of BPA treatment on transcription and transcription factor distribution using RNA-seq,
ATAC-seq and ChIP-seq in primordial germ cells and spermatogonial stem cells. Similar
analyses will be performed in adipocytes of obese mice in order to understand which of these
epigenetic alterations are maintained in adult tissues and may be responsible for the observed
obese phenotype. Results from this work will give critical insights into the mechanisms by which
alterations in the epigenome are established and transmitted between generations.

## Key facts

- **NIH application ID:** 9899105
- **Project number:** 5R01ES027859-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Victor G. Corces
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,317
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899105

## Citation

> US National Institutes of Health, RePORTER application 9899105, Mechanisms of transgenerational epigenetic inheritance (5R01ES027859-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899105. Licensed CC0.

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